Salts and solid forms of (S)-3-(4-((4-(morpholinomethyl)benzyl) oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and compositions comprising and methods of using the same

ABSTRACT

Salts and solid forms of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione, or a stereoisomer thereof, are disclosed. Compositions comprising and methods of using the salts and solid forms are also disclosed.

The present application is a continuation application of U.S. patentapplication Ser. No. 15/856,845, filed Dec. 28, 2017, which is acontinuation application of U.S. patent application Ser. No. 15/445,070,filed Feb. 28, 2017, now U.S. Pat. No. 9,884,062, which is acontinuation application of U.S. patent application Ser. No. 14/945,147,filed Nov. 18, 2015, now U.S. Pat. No. 9,629,849, which is acontinuation application of U.S. patent application Ser. No. 13/962,745,filed on Aug. 8, 2013, now U.S. Pat. No. 9,221,788, which claimspriority to U.S. Provisional Patent Application No. 61/681,484, filedAug. 9, 2012, the entirety of each of which is incorporated herein byreference.

1. FIELD

Provided herein are salts and solid forms of the compound of formula (I)or a stereoisomer thereof, solid forms of the salts, and methods ofsynthesizing the salts and solid forms.

Also provided herein are pharmaceutical compositions comprising thesalts and solid forms and methods for treating, preventing, and managingvarious disorders using the compositions, salts, and solid forms.

2. BACKGROUND

(a) Pathobiology of Cancer and Other Diseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties, including tumor necrosis factor α (TNF-α).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia;arthritis; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNF-α, may be useful in thetreatment and prevention of various diseases and conditions.

(b) Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health or age of a patient ormay be unacceptable to the patient.

Additionally, surgery may not completely remove neoplastic tissue.Radiation therapy is only effective when the neoplastic tissue exhibitsa higher sensitivity to radiation than normal tissue. Radiation therapycan also often elicit serious side effects. Hormonal therapy is rarelygiven as a single agent. Although hormonal therapy can be effective, itis often used to prevent or delay recurrence of cancer after othertreatments have removed the majority of cancer cells. Biologicaltherapies and immunotherapies are limited in number and may produce sideeffects such as rashes or swellings, flu-like symptoms, including fever,chills and fatigue, digestive tract problems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, N.Y.).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for safe and effective methods oftreating, preventing and managing cancer and other diseases andconditions, including for diseases that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy, while reducing or avoiding the toxicities and/or sideeffects associated with the conventional therapies.

(c) Salts and Solid Forms

Compounds having a basic moiety can form various salts with acids.Different salts of a given compound may have different properties thataffect the compound's stability, processability, in vivo performance asa pharmaceutical. The physical properties of certain salts of a givencompound may also allow for or facilitate the isolation of optically orstereomerically pure forms of the compound.

Compounds may also exist in different solid forms. The selection of asolid form of a pharmaceutical compound may affect a variety of physicaland chemical properties, which may provide benefits or drawbacks inprocessing, formulation, stability and bioavailability, among otherimportant pharmaceutical characteristics. Potential pharmaceuticalsolids include crystalline solids and amorphous solids. Amorphous solidsare characterized by a lack of long-range structural order, whereascrystalline solids are characterized by structural periodicity. Thedesired class of pharmaceutical solid depends upon the specificapplication; amorphous solids are sometimes selected on the basis of,e.g., an enhanced dissolution profile, while crystalline solids may bedesirable for properties such as, e.g., physical or chemical stability(see, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv. Rev., (2001)48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42).

Whether crystalline or amorphous, potential solid forms of apharmaceutical compound may include single-component andmultiple-component solids. Single-component solids consist essentiallyof the pharmaceutical compound in the absence of other compounds.Variety among single-component crystalline materials may potentiallyarise from the phenomenon of polymorphism, wherein multiplethree-dimensional arrangements exist for a particular pharmaceuticalcompound (see, e.g., S. R. Byrn et al., Solid State Chemistry of Drugs,(1999) SSCI, West Lafayette).

Additional diversity among the potential solid forms of a pharmaceuticalcompound may arise from the possibility of multiple-component solids.Crystalline solids comprising two or more ionic species are termed salts(see, e.g., Handbook of Pharmaceutical Salts: Properties, Selection andUse, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim).Additional types of multiple-component solids that may potentially offerother property improvements for a pharmaceutical compound or saltthereof include, e.g., hydrates, solvates, co-crystals and clathrates,among others (see, e.g., S. R. Byrn et al., Solid State Chemistry ofDrugs, (1999) SSCI, West Lafayette). Moreover, multiple-componentcrystal forms may potentially be susceptible to polymorphism, wherein agiven multiple-component composition may exist in more than onethree-dimensional crystalline arrangement. The discovery of solid formsis of great importance in the development of a safe, effective, stableand marketable pharmaceutical compound.

3. SUMMARY

Provided herein are salts and solid forms of the compound of formula (I)or a stereoisomer thereof, solid forms of the salts, and methods ofsynthesizing the salts and solid forms.

In one embodiment, provided herein are salts and solid forms of theracemic compound of formula (I), solid forms of the salts, and methodsof synthesizing the salts and solid forms. In one embodiment, providedherein are solid forms comprising the racemic Compound of formula (I)and a significant quantity of one or more additional species, such asions and/or molecules.

In one embodiment, provided herein are salts and solid forms of thecompound of formula (I-S), solid forms of the salts, and methods ofsynthesizing the salts and solid forms. In one embodiment, providedherein are solid forms comprising the Compound of formula (I-S) and asignificant quantity of one or more additional species, such as ionsand/or molecules.

The solids forms provided herein include, but are not limited to,hydrates, anhydrates, solvates, as well as crystal and amorphous forms.The solid forms provided herein are useful as active pharmaceuticalingredients for the preparation of formulations for use in animals orhumans. Thus, embodiments herein encompass the use of these solid formsas a final drug product. Certain embodiments provide solid forms usefulin making final dosage forms with improved properties, e.g., powder flowproperties, compaction properties, tableting properties, stabilityproperties, and excipient compatibility properties, among others, thatare needed for manufacturing, processing, formulation and/or storage offinal drug products. Certain embodiments herein provide pharmaceuticalcompositions comprising a single-component crystal form, amultiple-component crystal form, a single-component amorphous formand/or a multiple-component amorphous form comprising the compound offormula (I) or a stereoisomer thereof and a pharmaceutically acceptablediluent, excipient or carrier.

Provided herein are also pharmaceutical compositions, single unit dosageforms, dosing regimens and kits comprising the salts and solid forms.

Provided herein are also methods for treating, preventing, and managingvarious disorders using the compositions, salts, and solid forms. Themethods comprise administering to a patient in need of such treatment ormanagement a therapeutically effective amount of a salt or solid formprovided herein. Further provided are methods of preventing variousdiseases and disorders, which comprise administering to a patient inneed of such prevention a prophylactically effective amount of a salt orsolid form provided herein.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a representative XRPD pattern of an anhydrate ofCompound (I-S).

FIG. 2 provides a representative DSC thermogram of an anhydrate ofCompound (I-S).

FIG. 3 provides a representative TGA thermogram of an anhydrate ofCompound (I-S).

FIG. 4 provides a representative DVS plot of an anhydrate of Compound(I-S).

FIG. 5 provides a representative XRPD pattern of a hydrate of Compound(I-S).

FIG. 6 provides a representative DSC thermogram of a hydrate of Compound(I-S).

FIG. 7 provides a representative TGA thermogram of a hydrate of Compound(I-S).

FIG. 8 provides a representative XRPD pattern of a THF solvate ofCompound (I-S).

FIG. 9 provides a representative DSC thermogram of a THF solvate ofCompound (I-S).

FIG. 10 provides a representative TGA thermogram of a THF solvate ofCompound (I-S).

FIG. 11 provides a representative XRPD pattern of a besylate salt ofCompound (I-S).

FIG. 12 provides a representative DSC thermogram of a besylate salt ofCompound (I-S).

FIG. 13 provides a representative TGA thermogram of a besylate salt ofCompound (I-S).

FIG. 14 provides a representative DVS plot of a besylate salt ofCompound (I-S).

FIG. 15 provides a representative ¹H-NMR spectrum of a besylate salt ofCompound (I-S).

FIG. 16 provides a representative XRPD pattern of a DMSO solvate of abesylate salt of Compound (I-S).

FIG. 17 provides a representative DSC thermogram of a DMSO solvate of abesylate salt of Compound (I-S).

FIG. 18 provides a representative TGA thermogram of a DMSO solvate of abesylate salt of Compound (I-S).

FIG. 19 provides a representative ¹H-NMR spectrum of a DMSO solvate of abesylate salt of Compound (I-S).

FIG. 20 provides a representative XRPD pattern of a D-tartrate salt ofCompound (I-S).

FIG. 21A provides a representative DSC thermogram of a D-tartrate saltof Compound (I-S).

FIG. 21B provides a representative TGA thermogram of a D-tartrate saltof Compound (I-S).

FIG. 22 provides a representative ¹H-NMR spectrum of a D-tartrate saltof Compound (I-S).

FIG. 23 provides a representative XRPD pattern of a hemi D-tartrate saltof Compound (I-S).

FIG. 24A provides a representative DSC thermogram of a hemi D-tartratesalt of Compound (I-S).

FIG. 24B provides a representative TGA thermogram of a hemi D-tartratesalt of Compound (I-S).

FIG. 25 provides a representative ¹H-NMR spectrum of a hemi D-tartratesalt of Compound (I-S).

FIG. 26 provides a representative XRPD pattern of a L-tartrate salt ofCompound (I-S).

FIG. 27A provides a representative DSC thermogram of a L-tartrate saltof Compound (I-S).

FIG. 27B provides a representative TGA thermogram of a L-tartrate saltof Compound (I-S).

FIG. 28 provides a representative ¹H-NMR spectrum of a L-tartrate saltof Compound (I-S).

FIG. 29 provides a representative XRPD pattern of a tosylate salt ofCompound (I-S).

FIG. 30A provides a representative DSC thermogram of a tosylate salt ofCompound (I-S).

FIG. 30B provides a representative TGA thermogram of a tosylate salt ofCompound (I-S).

FIG. 31 provides a representative ¹H-NMR spectrum of a tosylate salt ofCompound (I-S).

FIG. 32 provides a representative XRPD pattern of a (+) camphorsulfonicacid salt of Compound (I-S).

FIG. 33 provides a representative DSC thermogram of a (+)camphorsulfonic acid salt of Compound (I-S).

FIG. 34 provides a representative TGA thermogram of a (+)camphorsulfonic acid salt of Compound (I-S).

FIG. 35 provides a representative ¹H-NMR spectrum of a (+)camphorsulfonic acid salt of Compound (I-S).

FIG. 36 provides a representative XRPD pattern of Form A of HCl salt ofCompound (I-S).

FIG. 37 provides a representative crystal habit of Form A of HCl salt ofCompound (I-S).

FIG. 38 provides a representative DSC thermogram of Form A of HCl saltof Compound (I-S).

FIG. 39 provides a representative TGA thermogram of Form A of HCl saltof Compound (I-S).

FIG. 40 provides a representative ¹H-NMR spectrum of Form A of HCl saltof Compound (I-S).

FIG. 41 provides a representative DVS plot of Form A of HCl salt ofCompound (I-S).

FIG. 42 provides representative XRPD patterns of Form A of HCl salt ofCompound (I-S) before and after undergoing absorption/desorption cycles.

FIG. 43 provides a representative XRPD pattern of Form A of HCl salt ofCompound (I-S) after application of 2000-psi for about 1 minute.

FIG. 44 provides a representative XRPD pattern of Form B of HCl salt ofCompound (I-S).

FIG. 45 provides a representative crystal habit of Form B of HCl salt ofCompound (I-S).

FIG. 46 provides a representative DSC thermogram of Form B of HCl saltof Compound (I-S).

FIG. 47 provides a representative TGA thermogram of Form B of HCl saltof Compound (I-S).

FIG. 48 provides a representative ¹H-NMR spectrum of Form B of HCl saltof Compound (I-S).

FIG. 49 provides a representative XRPD pattern of Form B of HCl salt ofCompound (I-S) after storage at ambient.

FIG. 50 provides a representative XRPD pattern of Form C of HCl salt ofCompound (I-S).

FIG. 51 provides a representative crystal habit of Form C of HCl salt ofCompound (I-S).

FIG. 52 provides a representative DSC thermogram of Form C of HCl saltof Compound (I-S).

FIG. 53 provides a representative TGA thermogram of Form C of HCl saltof Compound (I-S).

FIG. 54 provides a representative XRPD pattern of Form C of HCl salt ofCompound (I-S) after being heated to 165° C.

FIG. 55 provides a representative ¹H-NMR spectrum of Form C of HCl saltof Compound (I-S).

FIG. 56 provides representative XRPD patterns of Form C of HCl salt ofCompound (I-S) before and after undergoing absorption/desorption cycles.

FIG. 57 provides a representative XRPD pattern of Form D of HCl salt ofCompound (I-S).

FIG. 58 provides a representative crystal habit of Form D of HCl salt ofCompound (I-S).

FIG. 59 provides a representative DSC thermogram of Form D of HCl saltof Compound (I-S).

FIG. 60 provides a representative TGA thermogram of Form D of HCl saltof Compound (I-S).

FIG. 61 provides a representative ¹H-NMR spectrum of Form D of HCl saltof Compound (I-S).

FIG. 62 provides a representative DVS plot of Form D of HCl salt ofCompound (I-S).

FIG. 63 provides representative XRPD patterns of Form D of HCl salt ofCompound (I-S) before and after undergoing absorption/desorption cycles.

FIG. 64 provides a representative XRPD pattern of Form E of HCl salt ofCompound (I-S).

FIG. 65 provides a representative crystal habit of Form E of HCl salt ofCompound (I-S).

FIG. 66 provides a representative DSC thermogram of Form E of HCl saltof Compound (I-S).

FIG. 67 provides a representative TGA thermogram of Form E of HCl saltof Compound (I-S).

FIG. 68 provides a representative ¹H-NMR spectrum of Form E of HCl saltof Compound (I-S).

FIG. 69 provides a representative DVS plot of Form E of HCl salt ofCompound (I-S).

FIG. 70 provides representative XRPD patterns of Form E of HCl salt ofCompound (I-S) before and after undergoing absorption/desorption cycles.

FIG. 71 provides a representative XRPD pattern of Form E of HCl salt ofCompound (I-S) after being heated to 120° C.

FIG. 72 provides a representative XRPD pattern of Form E of HCl salt ofCompound (I-S) after being heated to 190° C.

FIG. 73 provides a representative XRPD pattern of Form F of HCl salt ofCompound (I-S).

FIG. 74 provides a representative crystal habit of Form F of HCl salt ofCompound (I-S).

FIG. 75 provides a representative DSC thermogram of Form F of HCl saltof Compound (I-S).

FIG. 76 provides a representative TGA thermogram of Form F of HCl saltof Compound (I-S).

FIG. 77 provides a representative ¹H-NMR spectrum of Form F of HCl saltof Compound (I-S).

FIG. 78 provides a representative DVS plot of Form F of HCl salt ofCompound (I-S).

FIG. 79 provides representative XRPD patterns of Form F of HCl salt ofCompound (I-S) before and after undergoing absorption/desorption cycles.

FIG. 80 provides a representative XRPD pattern of Form F of HCl salt ofCompound (I-S) after being heated to 120° C.

FIG. 81 provides a representative TGA thermogram of Form F of HCl saltof Compound (I-S) after being heated to 120° C.

FIG. 82 provides a representative XRPD pattern of Form G of HCl salt ofCompound (I-S).

FIG. 83 provides a representative DSC thermogram of Form G of HCl saltof Compound (I-S).

FIG. 84 provides a representative TGA thermogram of Form G of HCl saltof Compound (I-S).

FIG. 85 provides a representative ¹H-NMR spectrum of Form G of HCl saltof Compound (I-S).

FIG. 86 provides a representative XRPD pattern of Form H of HCl salt ofCompound (I-S).

FIG. 87 provides a representative DSC thermogram of Form H of HCl saltof Compound (I-S).

FIG. 88 provides a representative TGA thermogram of Form H of HCl saltof Compound (I-S).

FIG. 89 provides a representative ¹H-NMR spectrum of Form H of HCl saltof Compound (I-S).

FIG. 90 provides a representative XRPD pattern of Form I of HCl salt ofCompound (I-S).

FIG. 91 provides a representative XRPD pattern of Form I of HCl salt ofCompound (I-S) after being washed with MeOAc.

FIG. 92 provides a representative XRPD pattern of Form J of HCl salt ofCompound (I-S).

FIG. 93 provides a representative DSC thermogram of Form J of HCl saltof Compound (I-S).

FIG. 94 provides a representative TGA thermogram of Form J of HCl saltof Compound (I-S).

FIG. 95 provides a representative XRPD pattern of Form K of HCl salt ofCompound (I-S).

FIG. 96 provides a representative XRPD pattern of Form K of HCl salt ofCompound (I-S) after storage at ambient.

FIG. 97 provides a representative XRPD pattern of an anhydrate ofracemic Compound (I).

FIG. 98A provides a representative DSC thermogram of an anhydrate ofracemic Compound (I).

FIG. 98B provides a representative TGA thermogram of an anhydrate ofracemic Compound (I).

FIG. 99 provides a representative XRPD pattern of a hydrate of racemicCompound (I).

FIG. 100A provides a representative DSC thermogram of a hydrate ofracemic Compound (I).

FIG. 100B provides a representative TGA thermogram of a hydrate ofracemic Compound (I).

FIG. 101 provides a representative XRPD pattern of a hydrate of HCl saltof racemic Compound (I).

FIG. 102A provides a representative DSC thermogram of a hydrate of HClsalt of racemic Compound (I).

FIG. 102B provides a representative TGA thermogram of a hydrate of HClsalt of racemic Compound (I).

FIG. 103 provides a representative DVS plot of a hydrate of HCl salt ofracemic Compound (I).

FIG. 104 provides a representative XRPD pattern of a MeOH solvate of HClsalt of racemic Compound (I).

FIG. 105 provides a representative XRPD stack plot of HCl salt forms ofCompound (I-S).

FIG. 106 provides an interconversion diagram of Form A-K of HCl salt ofCompound (I-S).

5. DETAILED DESCRIPTION 5.1 Salts and Solid Forms of Compound (I-S) andSyntheses Thereof

Compound (I-S) is the (S) stereoisomer of3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione.Methods of preparing racemic3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehave been reported in U.S. Patent Publication No. 2011/0196150, which isincorporated herein by reference in its entirety. Compound (I-S) has thefollowing structure:

Provided herein are salts of Compound (I-S). In some embodiments,Compound (I-S) is a salt of H-X, wherein X is F, Cl, Br, I, RSO₃, orRCO₂, wherein R is alkyl, aryl, substituted alkyl, substituted aryl, orhydroxy. In some embodiments, Compound (I-S) is a tartrate salt, e.g., Dor L, or hemi-tartrate salt. In some embodiments, the salt is ahydrochloric acid, benzenesulfonic acid, p-toluenesulfonic acid, (+)camphorsulfonic acid salt, D-tartaric acid, or L-tartaric acid salt. Insome embodiments, the salt is a carbonate salt or a sulfate salt.Without being limited by any particular theory, the acids are associatedwith the basic nitrogen of the nitrogen on the morpholine ring ofCompound (I-S).

Also provided herein are solid forms of Compound (I-S) and of salts ofCompound (I-S). In some embodiments, the solid form is an anhydrate,hydrate, or solvate. In some embodiments, the solvate is atetrahydrofuran or dimethyl sulfoxide solvate.

As used herein and unless otherwise specified, the terms “solid form”and related terms refer to a physical form which is not predominantly ina liquid or a gaseous state. Solid forms may be crystalline, amorphousor mixtures thereof. In particular embodiments, solid forms may beliquid crystals.

In some embodiments, Compound (I-S) is a single component or multiplecomponent solid form. A “single-component” solid form comprisingCompound (I-S) consists essentially of Compound (I-S). A“multiple-component” solid form comprising Compound (I-S) comprises asignificant quantity of one or more additional species, such as ionsand/or molecules, within the solid form. For example, in particularembodiments, a crystalline multiple-component solid form comprisingCompound (I-S) further comprises one or more species non-covalentlybonded at regular positions in the crystal lattice. In one embodiment, amultiple component solid form provided herein is a co-crystal.

As used herein and unless otherwise specified, the term “crystalline”and related terms used herein, when used to describe a substance,modification, material, component or product, unless otherwisespecified, mean that the substance, modification, material, component orproduct is substantially crystalline as determined by X-ray diffraction.See, e.g., Remington: The Science and Practice of Pharmacy, 21^(st)edition, Lippincott, Williams and Wilkins, Baltimore, Md. (2005); TheUnited States Pharmacopeia, 23^(rd) edition, 1843-1844 (1995).

As used herein and unless otherwise specified, the term “crystal forms”and related terms herein refer to solid forms that are crystalline.Crystal forms include single-component crystal forms andmultiple-component crystal forms, and include, but are not limited to,polymorphs, solvates, hydrates, and other molecular complexes, as wellas salts, solvates of salts, hydrates of salts, other molecularcomplexes of salts, and polymorphs thereof. In certain embodiments, acrystal form of a substance may be substantially free of amorphous formsand/or other crystal forms. In certain embodiments, a crystal form of asubstance may contain less than about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%,9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or moreamorphous forms and/or other crystal forms on a weight basis. In certainembodiments, a crystal form of a substance may be physically and/orchemically pure. In certain embodiments, a crystal form of a substancemay be about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90%physically and/or chemically pure.

Also provided herein are polymorphs of various salts of Compound (I-S).As used herein and unless otherwise specified, the terms “polymorphs,”“polymorphic forms” and related terms herein, refer to two or morecrystal forms that consist essentially of the same molecule, moleculesor ions. Like different crystal forms, different polymorphs may havedifferent physical properties such as, for example, meltingtemperatures, heats of fusion, solubilities, dissolution rates and/orvibrational spectra, as a result of the arrangement or conformation ofthe molecules and/or ions in the crystal lattice. The differences inphysical properties may affect pharmaceutical parameters such as storagestability, compressibility and density (important in formulation andproduct manufacturing), and dissolution rate (an important factor inbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical changes (e.g., tabletscrumble on storage as a kinetically favored polymorph converts to athermodynamically more stable polymorph) or both (e.g., tablets of onepolymorph are more susceptible to breakdown at high humidity). As aresult of solubility/dissolution differences, in the extreme case, somesolid-state transitions may result in lack of potency or, at the otherextreme, toxicity. In addition, the physical properties may be importantin processing (for example, one polymorph might be more likely to formsolvates or might be difficult to filter and wash free of impurities,and particle shape and size distribution might be different betweenpolymorphs).

As used herein and unless otherwise specified, the term “solvate” and“solvated,” refer to a crystal form of a substance which containssolvent. The term “hydrate” and “hydrated” refer to a solvate whereinthe solvent comprises water. “Polymorphs of solvates” refers to theexistence of more than one crystal form for a particular solvatecomposition. Similarly, “polymorphs of hydrates” refers to the existenceof more than one crystal form for a particular hydrate composition. Theterm “desolvated solvate,” as used herein, refers to a crystal form of asubstance which may be prepared by removing the solvent from a solvate.

As used herein and unless otherwise specified, the term “amorphous,”“amorphous form,” and related terms used herein, mean that thesubstance, component or product in question is not substantiallycrystalline as determined by X-ray diffraction. In particular, the term“amorphous form” describes a disordered solid form, i.e., a solid formlacking long range crystalline order. In certain embodiments, anamorphous form of a substance may be substantially free of otheramorphous forms and/or crystal forms. In other embodiments, an amorphousform of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more other amorphousforms and/or crystal forms on a weight basis. In certain embodiments, anamorphous form of a substance may be physically and/or chemically pure.In certain embodiments, an amorphous form of a substance may be about99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% physically and/orchemically pure.

Techniques for characterizing crystal forms and amorphous forms include,but are not limited to, thermal gravimetric analysis (TGA), differentialscanning calorimetry (DSC), X-ray powder diffractometry (XRPD),single-crystal X-ray diffractometry, vibrational spectroscopy, e.g.,infrared (IR) and Raman spectroscopy, solid-state and solution nuclearmagnetic resonance (NMR) spectroscopy, optical microscopy, hot stageoptical microscopy, scanning electron microscopy (SEM), electroncrystallography and quantitative analysis, particle size analysis (PSA),surface area analysis, solubility measurements, dissolutionmeasurements, elemental analysis and Karl Fischer analysis.Characteristic unit cell parameters may be determined using one or moretechniques such as, but not limited to, X-ray diffraction and neutrondiffraction, including single-crystal diffraction and powderdiffraction. Techniques useful for analyzing powder diffraction datainclude profile refinement, such as Rietveld refinement, which may beused, e.g., to analyze diffraction peaks associated with a single phasein a sample comprising more than one solid phase. Other methods usefulfor analyzing powder diffraction data include unit cell indexing, whichallows one of skill in the art to determine unit cell parameters from asample comprising crystalline powder.

As used herein and unless otherwise specified, the terms “about” and“approximately,” when used in connection with a numeric value or a rangeof values which is provided to characterize a particular solid form,e.g., a specific temperature or temperature range, such as, for example,that describing a melting, dehydration, desolvation or glass transitiontemperature; a mass change, such as, for example, a mass change as afunction of temperature or humidity; a solvent or water content, interms of, for example, mass or a percentage; or a peak position, suchas, for example, in analysis by IR or Raman spectroscopy or XRPD;indicate that the value or range of values may deviate to an extentdeemed reasonable to one of ordinary skill in the art while stilldescribing the particular solid form. For example, in particularembodiments, the terms “about” and “approximately,” when used in thiscontext, indicate that the numeric value or range of values may varywithin 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%,0.5%, or 0.25% of the recited value or range of values. As used herein,a tilde (i.e., “˜”) preceding a numerical value or range of valuesindicates “about” or “approximately.”

In some embodiments, the solid forms, e.g., crystal or amorphous forms,described herein are substantially pure, i.e., substantially free ofother solid forms and/or of other chemical compounds, containing lessthan about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.75%, 0.5%, 0.25% or 0.1% percent by weight of one or more other solidforms and/or of other chemical compounds.

Solid forms may exhibit distinct physical characterization data that areunique to a particular solid form, such as the crystal forms describedherein. These characterization data may be obtained by varioustechniques known to those skilled in the art, including for exampleX-ray powder diffraction, differential scanning calorimetry, thermalgravimetric analysis, and nuclear magnetic resonance spectroscopy. Thedata provided by these techniques may be used to identify a particularsolid form. One skilled in the art can determine whether a solid form isone of the forms described herein by performing one of thesecharacterization techniques and determining whether the resulting data“matches” the reference data provided herein, which is identified asbeing characteristic of a particular solid form. Characterization datathat “matches” those of a reference solid form is understood by thoseskilled in the art to correspond to the same solid form as the referencesolid form. In analyzing whether data “match,” a person of ordinaryskill in the art understands that particular characterization datapoints may vary to a reasonable extent while still describing a givensolid form, due to, for example, experimental error and routinesample-to-sample analysis.

The solid forms provided herein may be crystalline, amorphous, or anintermediate form. The crystal forms described herein, therefore, mayhave varying degrees of crystallinity or lattice order. The solid formsdescribed herein are not limited by any particular degree ofcrystallinity or lattice order, and may be 0-100% crystalline. Methodsof determining the degree of crystallinity are known to those ofordinary skill in the, such as those described in Suryanarayanan, R.,X-Ray Power Diffractometry, Physical Characterization of PharmaceuticalSalts, H. G. Brittain, Editor, Mercel Dekkter, Murray Hill, N.J., 1995,pp. 187-199, which is incorporated herein by reference in its entirety.In some embodiments, the solid forms described herein are about 0, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95or 100% crystalline.

(1) Freebase Anhydrate

Provided herein is an anhydrate of Compound (I-S). In some embodiments,the anhydrate is obtained by heating a mixture of Compound (I-S) andacetonitrile. In some embodiments, the anhydrate is obtained by heatinga mixture of Compound (I-S) and acetonitrile to about 40° C. andsubsequently cooling the mixture to about room temperature. In someembodiments, the anhydrate is obtained by heating a mixture of Compound(I-S) and acetonitrile to about 40° C., subsequently cooling the mixtureto about room temperature, and isolating the anhydrate by filtration.

Without being limited by any particular theory, in some embodiments, theanhydrate has the following formula:

A representative XRPD pattern of the anhydrate of Compound (I-S) isprovided in FIG. 1.

In some embodiments, provided herein is a solid form comprising Compound(I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6, 7, or allof the following or approximately the following positions: 4.76, 7.15,8.72, 12.10, 14.31, 14,96, 19.06, and 26.11 degrees 2θ. In oneembodiment, the solid form is characterized by 3 of the peaks. Inanother embodiment, the solid form is characterized by 5 of the peaks.In another embodiment, the solid form is characterized by all of thepeaks.

In some embodiments, provided herein is a solid form comprising Compound(I-S) having an XRPD pattern comprising peaks at approximately 4.76,8.72, 14.31, and 14.96 degrees 2θ. In certain embodiments, the solidform further comprises peaks at approximately 7.15, 12.10, 19.06, and26.11 degrees 2θ. In some embodiments, the solid form comprises peaks at4.76, 7.15, 8.72, 12.10, 14.31, 14.96, 19.06, and 26.11 degrees 2θ.

In some embodiments, provided herein is a solid form comprising Compound(I-S), wherein the solid form is characterized by an XRPD diffractionpattern which matches the XRPD pattern presented in FIG. 1.

Representative thermal characteristics of the anhydrate are provided inFIG. 2 and FIG. 3. A representative differential scanning calorimetry(DSC) thermogram is presented in FIG. 2. In some embodiments, providedherein is a solid form comprising Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 133° C.and an onset temperature of about 127° C., with a peak temperature ofabout 155° C., or with a peak temperature of about 215° C. In someembodiments, provided herein is a solid form comprising Compound (I-S)that exhibits thermal events, as characterized by DSC, with a peaktemperature of about 133° C. and an onset temperature of about 127° C.,with a peak temperature of about 155° C., and with a peak temperature ofabout 215° C. In certain embodiments, the event with a peak temperatureof about 133° C. corresponds to melting. In certain embodiments, theevent with a peak temperature of about 155° C. corresponds toepimerization and crystallization. In certain embodiments, the eventwith a peak temperature of about 215° C. corresponds to melting. In someembodiments, provided herein is a solid form comprising Compound (I-S),wherein the solid form is characterized by a DSC thermogram whichmatches the DSC thermogram presented in FIG. 2.

A representative thermal gravimetric analysis curve of the anhydrate isprovided in FIG. 3, which exhibits no substantial change of the totalsample weight upon heating from about 25 to about 150° C. In someembodiments, provided herein is a solid form comprising Compound (I-S),wherein the solid form is characterized by a TGA thermogram whichmatches the TGA thermogram presented in FIG. 3.

A representative DVS isotherm plot of the anhydrate is provided in FIG.4. In some embodiments, provided herein is a solid form comprisingCompound (I-S), wherein the solid form is characterized by a DVSisotherm plot which matches the DVS isotherm plot presented in FIG. 4.

(ii) Freebase Hydrate

Provided herein is a hydrate of Compound (I-S). Furthermore, providedherein is a solid form comprising Compound (I-S) and water. In someembodiments, the solid form is obtained by heating a mixture of Compound(I-S) and water. In some embodiments, the solid form is obtained byheating a mixture of Compound (I-S) and water to about 50° C. andsubsequently cooling the mixture to about room temperature. In someembodiments, the solid form is obtained by heating a mixture of Compound(I-S) and water to about 50° C., subsequently cooling the mixture toabout room temperature, and isolating the solid form by filtration. Insome embodiments, the molar ratio of Compound (I-S) to water isapproximately 2:1 to 1:2. In some embodiments, the molar ratio ofCompound (I-S) to water is approximately 1:1.

Without being limited by any particular theory, in some embodiments thehydrate has the following formula:

A representative XRPD pattern of a hydrate of Compound (I-S) is providedin FIG. 5.

In some embodiments, provided herein is a solid form comprising Compound(I-S) and water characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, or all of the following or approximately thefollowing positions: 8.31, 11.80, 13.42, 13.79, 15.92, 17.15, 17.37,18.31, 20.41, 22.07, 25.58, 26.00, and 27.14 degrees 2θ. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 10 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising Compound(I-S) and water having an XRPD pattern comprising peaks at approximately8.31, 11.80, and 17.37 degrees 2θ. In certain embodiments, the solidform further comprises peaks at approximately 13.79, 17.15, 26.00degrees 2θ. In one embodiment, the solid form comprises peaks atapproximately 8.31, 11.80, 13.42, 13.79, 15.92, 17.15, 17.37, 18.31,20.41, 22.07, 25.58, 26.00, and 27.14 degrees 2θ.

In some embodiments, provided herein is a solid form comprising Compound(I-S) and water, wherein the solid form is characterized by an XRPDdiffraction pattern which matches the XRPD pattern presented in FIG. 5.

Representative thermal characteristics of the hydrate are provided inFIG. 6 and FIG. 7. A representative differential scanning calorimetry(DSC) thermogram is presented in FIG. 6 ° C. In some embodiments,provided herein is a solid form comprising Compound (I-S) and water thatexhibits a thermal event, as characterized by DSC, with a peaktemperature of about 110° C., with a peak temperature of about 188° C.and an onset temperature of about 180° C., or with a peak temperature ofabout 220° C. and an onset temperature of about 217° C. In someembodiments, provided herein is a solid form comprising Compound (I-S)and water that exhibits thermal events, as characterized by DSC, with apeak temperature of about 110° C., with a peak temperature of about 188°C. and an onset temperature of about 180° C., and with a peaktemperature of about 220° C. and an onset temperature of about 217° C.In some embodiments, provided herein is a solid form comprising Compound(I-S) and water, wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 6.

A representative thermal gravimetric analysis curve of the hydrate isprovided in FIG. 7, which exhibits a weight loss of about 5.43% of thetotal sample weight upon heating from about 30 to about 150° C. In someembodiments, provided herein is a solid form comprising Compound (I-S)and water, wherein the solid form is characterized by a TGA thermogramwhich matches the TGA thermogram presented in FIG. 7.

(iii) Freebase THF Solvate

Provided herein is a tetrahydrofuran (THF) solvate of Compound (I-S).Furthermore, provided herein is a solid form comprising Compound (I-S)and THF. In some embodiments, the solid form is obtained by heating amixture of Compound (I-S) and THF. In some embodiments, the solid formis obtained by heating a mixture of Compound (I-S) and THF to about 40°C. and subsequently cooling the mixture to about room temperature. Insome embodiments, the solid form is obtained by heating a mixture ofCompound (I-S) and THF to about 40° C., subsequently cooling the mixtureto about room temperature, and isolating the solid form by filtration.In some embodiments, the molar ratio of Compound (I-S) to THF isapproximately 2:1 to 1:2. In some embodiments, the molar ratio ofCompound (I-S) to THF is approximately 1:1.

Without being limited by any particular theory, in some embodiments, thesolvate has the following formula:

A representative XRPD pattern of a THF solvate of Compound (I-S) isprovided in FIG. 8.

In some embodiments, provided herein is a solid form comprising Compound(I-S) and THF characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14 or all of the following or approximately thefollowing positions: 6.03, 8.65, 10.40, 11.80, 15.12, 17.71, 17.90,18.23, 18.59, 20.49, 20.89, 22.16, 23.24, 26.47, and 29.14 degrees 2θ.In some embodiments, the solid form is characterized by 3 of the peaks.In some embodiments, the solid form is characterized by 5 of the peaks.In some embodiments, the solid form is characterized by 7 of the peaks.In some embodiments, the solid form is characterized by 10 of the peaks.In some embodiments, the solid form is characterized by 13 of the peaks.In some embodiments, the solid form is characterized by all of thepeaks.

In some embodiments, provided herein is a solid form comprising Compound(I-S) and THF having an XRPD pattern comprising peaks at approximately11.80, 20.89, and 22.16 degrees 2θ. In certain embodiments, the solidform further comprises peaks at approximately 6.03 and 18.59 degrees 2θ.In one embodiment, the solid form comprises peaks at approximately 6.03,8.65, 10.40, 11.80, 15.12, 17.71, 17.90, 18.23, 18.59, 20.49, 20.89,22.16, 23.24, 26.47, and 29.14 degrees 2θ.

In some embodiments, provided herein is a solid form comprising Compound(I-S) and THF, wherein the solid form is characterized by an XRPDdiffraction pattern which matches the XRPD pattern presented in FIG. 8.

Representative thermal characteristics of the solvate are provided inFIG. 9 and FIG. 10. A representative differential scanning calorimetry(DSC) thermogram is presented in FIG. 9. In some embodiments, providedherein is a solid form comprising Compound (I-S) and THF that exhibits athermal event, as characterized by DSC, with a peak temperature of about114° C. and an onset temperature of about 105° C., with a peaktemperature of about 177° C. and an onset temperature of about 171° C.,or with a peak temperature of about 219° C. and an onset temperature ofabout 219° C. In some embodiments, provided herein is a solid formcomprising Compound (I-S) and THF that exhibits thermal events, ascharacterized by DSC, with a peak temperature of about 114° C. and anonset temperature of about 105° C., with a peak temperature of about177° C. and an onset temperature of about 171° C., and with a peaktemperature of about 219° C. and an onset temperature of about 219° C.In some embodiments, provided herein is a solid form comprising Compound(I-S) and THF, wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 9.

A representative thermal gravimetric analysis curve of the solvate isprovided in FIG. 10, which exhibits a weight loss of about 11.51% of thetotal sample weight upon heating from about 50 to about 175° C. In someembodiments, provided herein is a solid form comprising Compound (I-S)and THF, wherein the solid form is characterized by a TGA thermogramwhich matches the TGA thermogram presented in FIG. 10.

(iv) Besylate

Provided herein is a solid form comprising a besylate salt of Compound(I-S). In some embodiments, the solid form is obtained by heating amixture of Compound (II), solvent, and benzenesulfonic acid, followed bycrystallization.

In some embodiments, the solvent is acetonitrile. In some embodiments,the solid form is obtained by the steps of (1) heating a mixture ofCompound (II), benzenesulfonic acid, and acetonitrile to about 82° C.and (2) crystallization. In some embodiments, the solid form is isolatedby filtration.

In some embodiments, the molar ratio of Compound (I-S) tobenzenesulfonic acid in the solid form is approximately 2:1 to 1:2. Insome embodiments, the molar ratio is approximately 1:1.

Without being limited by any particular theory, in some embodiments, thebesylate has the following formula:

A representative XRPD pattern of the besylate Compound (I-S) is providedin FIG. 11.

In some embodiments, provided herein is a solid form comprising abesylate salt of Compound (I-S) characterized by XRPD peaks located at1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25 or all of the following or approximately thefollowing positions 7.06, 7.69, 9.51, 9.99, 15.48, 15.92, 16.42, 18.28,19.07, 20.36, 20.71, 21.34, 21.66, 22.33, 22.52, 23.60, 23.96, 24.31,24.44, 25.14, 25.32, 26.02, 27.58, 27.99, 28.36, and 29.82 degrees 2θ.In some embodiments, the solid form is characterized by 3 of the peaks.In some embodiments, the solid form is characterized by 5 of the peaks.In some embodiments, the solid form is characterized by 7 of the peaks.In some embodiments, the solid form is characterized by 9 of the peaks.In some embodiments, the solid form is characterized by 11 of the peaks.In some embodiments, the solid form is characterized by 13 of the peaks.In some embodiments, the solid form is characterized by 15 of the peaks.In some embodiments, the solid form is characterized by 17 of the peaks.In some embodiments, the solid form is characterized by all of thepeaks.

In some embodiments, provided herein is a solid form comprising besylateof Compound (I-S) having an XRPD pattern comprising peaks atapproximately 19.07, 20.71, and 23.96 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately15.48 and 15.92 degrees 2θ. In one embodiment, the solid form comprisespeaks at approximately 7.06, 7.69, 9.51, 9.99, 15.48, 15.92, 16.42,18.28, 19.07, 20.36, 20.71, 21.34, 21.66, 22.33, 22.52, 23.60, 23.96,24.31, 24.44, 25.14, 25.32, 26.02, 27.58, 27.99, 28.36, and 29.82degrees 2θ.

In some embodiments, provided herein is a solid form comprising abesylate salt of Compound (I-S), wherein the solid form is characterizedby an XRPD diffraction pattern which matches the XRPD pattern presentedin FIG. 11.

Representative thermal characteristics of the besylate are provided inFIG. 12 and FIG. 13. A representative differential scanning calorimetry(DSC) thermogram is presented in FIG. 12. In some embodiments, providedherein is a solid form comprising a besylate salt of Compound (I-S) thatexhibits a thermal event, as characterized by DSC, with a peaktemperature of about 220° C. and an onset temperature of about 211° C.In some embodiments, provided herein is a solid form comprising abesylate salt of Compound (I-S), wherein the solid form is characterizedby a DSC thermogram which matches the DSC thermogram presented in FIG.12.

A representative thermal gravimetric analysis curve of the besylate saltof Compound (I-S) is provided in FIG. 13, which exhibits no substantialchange of the total sample weight upon heating from about 30 to about125° C. In some embodiments, provided herein is a solid form comprisinga besylate salt of Compound (I-S), wherein the solid form ischaracterized by a TGA thermogram which matches the TGA thermogrampresented in FIG. 13.

A representative DVS isotherm plot of the besylate salt of Compound(I-S) is provided in FIG. 14. In some embodiments, provided herein is asolid form comprising a besylate salt of Compound (I-S), wherein thesolid form is characterized by a DVS isotherm plot which matches the DVSisotherm plot presented in FIG. 14.

A representative ¹H-NMR spectrum of the besylate salt of Compound (I-S)is provided in FIG. 15. In some embodiments, provided herein is a solidform comprising a besylate salt of Compound (I-S), wherein the solidform is characterized by a ¹H-NMR spectrum which matches the ¹H-NMRspectrum presented in FIG. 15.

(v) Besylate DMSO Solvate

Provided herein is a solid form comprising a DMSO solvate of thebesylate salt of Compound (I-S).

In some embodiments, the solid form is obtained by contacting a besylatesalt of Compound (I-S) with in DMSO and solvent. In some embodiments,the solvent in ethyl acetate.

In some embodiments, the molar ratio of Compound (I-S) tobenzenesulfonic acid in the solid form is approximately 2:1 to 1:2. Insome embodiments, the molar ratio is approximately 1:1.

In some embodiments, the molar ratio of Compound (I-S) to DMSO in thesolid form is approximately 2:1 to 1:2. In some embodiments, the molarratio is approximately 1:1.

Without being limited by any particular theory, in some embodiments, thesolvate has the following formula:

A representative XRPD pattern of the solvate is provided in FIG. 16.

In some embodiments, provided herein is a solid form comprising a DMSOsolvate of a besylate salt of Compound (I-S) characterized by XRPD peakslocated at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all ofthe following or approximately the following positions 7.31, 12.17,14.94, 16.02, 16.58, 16.88, 18.14, 20.02, 21.10, 22.68, 23.04, 24.22,24.49, 24.99, 26.70, and 28.52 degrees 2θ. In some embodiments, thesolid form is characterized by 3 of the peaks. In some embodiments, thesolid form is characterized by 5 of the peaks. In some embodiments, thesolid form is characterized by 7 of the peaks. In some embodiments, thesolid form is characterized by 9 of the peaks. In some embodiments, thesolid form is characterized by 11 of the peaks. In some embodiments, thesolid form is characterized by 13 of the peaks. In some embodiments, thesolid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a DMSOsolvate of a besylate of Compound (I-S) having an XRPD patterncomprising peaks at approximately 16.88, 18.14, and 20.02 degrees 2θ. Incertain embodiments, the solid form further comprises peaks atapproximately 7.31 and 24.49 degrees 2θ. In one embodiment, the solidform comprises peaks at approximately 7.31, 12.17, 14.94, 16.02, 16.58,16.88, 18.14, 20.02, 21.10, 22.68, 23.04, 24.22, 24.49, 24.99, 26.70,and 28.52 degrees 2θ.

In some embodiments, provided herein is a solid form comprising a DMSOsolvate of a besylate salt of Compound (I-S), wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 26.

Representative thermal characteristics of the DMSO solvate are providedin FIG. 17 and FIG. 18. A representative differential scanningcalorimetry (DSC) thermogram is presented in FIG. 17. In someembodiments, provided herein is a solid form comprising a DMSO solvateof a besylate salt of Compound (I-S) that exhibits a thermal event, ascharacterized by DSC, with a peak temperature of about 146° C. and anonset temperature of about 143° C. In some embodiments, provided hereinis a solid form comprising a DMSO solvate of a besylate salt of Compound(I-S), wherein the solid form is characterized by a DSC thermogram whichmatches the DSC thermogram presented in FIG. 17.

A representative thermal gravimetric analysis curve of the DMSO solvateof the besylate salt of Compound (I-S) is provided in FIG. 18, whichexhibits no substantial change of the total sample weight upon heatingfrom about 15 to about 110° C. In some embodiments, provided herein is asolid form comprising a DMSO solvate of a besylate salt of Compound(I-S), wherein the solid form is characterized by a TGA thermogram whichmatches the TGA thermogram presented in FIG. 18.

A representative spectrum of the DMSO solvate of the besylate salt ofCompound (I-S) is provided in FIG. 19. In some embodiments, providedherein is a solid form comprising a DMSO solvate of a besylate salt ofCompound (I-S), wherein the solid form is characterized by a ¹H-NMRspectrum which matches the ¹H-NMR spectrum presented in FIG. 19.

(vi) D-Tartrate

Provided herein is a solid form comprising a D-tartrate salt of Compound(I-S).

In some embodiments, the solid form is obtained by heating a mixture ofCompound (I-S) with D-tartaric acid and solvent. In some embodiments,the solvent in acetonitrile. In some embodiments, the mixture is heatedto about 70° C. In some embodiments, solvent is acetonitrile and themixture is heated to about 70° C. for about 5 hours, then maintained atabout 50° C. for about 14 hours, and subsequently cooled. In someembodiments, the solid form is isolated by filtration.

In some embodiments, the molar ratio is approximately 1:1.

Without being limited by any particular theory, in some embodiments, thetartrate has the following formula:

A representative XRPD pattern of the tartrate salt is provided in FIG.20.

In some embodiments, provided herein is a solid form comprising aD-tartrate salt of Compound (I-S) characterized by XRPD peaks located at1, 2, 3, 4, 5, 6, 7, 8, or all of the following or approximately thefollowing positions 6.84, 17.00, 18.01, 19.25, 19.73, 20.51, 21.25,21.67, and 25.86 degrees 2θ. In some embodiments, the solid form ischaracterized by 3 of the peaks. In some embodiments, the solid form ischaracterized by 5 of the peaks. In some embodiments, the solid form ischaracterized by 7 of the peaks. In some embodiments, the solid form ischaracterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising aD-tartrate salt of Compound (I-S) having an XRPD pattern comprisingpeaks at approximately 17.00, 19.73, and 25.86 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately19.25 and 21.25 degrees 2θ. In one embodiment, the solid form comprisespeaks at approximately positions 6.84, 17.00, 18.01, 19.25, 19.73,20.51, 21.25, 21.67, and 25.86 degrees 2θ.

In some embodiments, provided herein is a solid form comprising aD-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 20.

Representative thermal characteristics of the D-tartrate salt areprovided in FIG. 21A and FIG. 21B. A representative differentialscanning calorimetry (DSC) thermogram is presented in FIG. 21A. In someembodiments, provided herein is a solid form comprising a D-tartratesalt of Compound (I-S) that exhibits a thermal event, as characterizedby DSC, with a peak temperature of about 181° C. In some embodiments,provided herein is a solid form comprising a D-tartrate salt of Compound(I-S), wherein the solid form is characterized by a DSC thermogram whichmatches the DSC thermogram presented in FIG. 21A.

A representative thermal gravimetric analysis curve of the D-tartratesalt is provided in FIG. 21B, which exhibits a weight loss of about28.91% of the total sample weight upon heating from about 140 to about250° C. In some embodiments, provided herein is a solid form comprisinga D-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by a TGA thermogram which matches the TGA thermogrampresented in FIG. 21B.

A representative spectrum of the D-tartrate salt of Compound (I-S) isprovided in FIG. 22. In some embodiments, provided herein is a solidform comprising a D-tartrate salt of Compound (I-S), wherein the solidform is characterized by a ¹H-NMR spectrum which matches the ¹H-NMRspectrum presented in FIG. 22.

(vii) Hemi D-Tartrate

Provided herein is a solid form comprising a hemi D-tartrate salt ofCompound (I-S).

In some embodiments, the solid form is obtained by heating a mixture ofCompound (I-S) with D-tartaric acid and solvent. In some embodiments,the solvent in acetonitrile. In some embodiments, the mixture is heatedto about 60° C. In some embodiments, solvent is acetonitrile and themixture is heated to about 60° C. for about 1 hour, then maintained atabout 75° C. for about 1 hour, and subsequently cooled. In someembodiments, the solid form is isolated by filtration.

In some embodiments, the molar ratio of Compound (I-S) to tartaric acidin the solid form is approximately 2:1.

Without being limited by any particular theory, in some embodiments, thehemi tartrate has the following formula:

A representative XRPD pattern of the hemi tartrate salt is provided inFIG. 23.

In some embodiments, provided herein is a solid form comprising a hemiD-tartrate salt of Compound (I-S) characterized by XRPD peaks located at1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all of thefollowing or approximately the following positions 6.21, 6.47, 9.94,12.32, 12.91, 16.32, 16.64, 17.73, 19.09, 19.78, 19.88, 21.32, 24.60,25.89, 26.00, and 27.54 degrees 2θ. In some embodiments, the solid formis characterized by 3 of the peaks. In some embodiments, the solid formis characterized by 5 of the peaks. In some embodiments, the solid formis characterized by 7 of the peaks. In some embodiments, the solid formis characterized by 9 of the peaks. In some embodiments, the solid formis characterized by 11 of the peaks. In some embodiments, the solid formis characterized by 13 of the peaks. In some embodiments, the solid formis characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a hemiD-tartrate salt of Compound (I-S) having an XRPD pattern comprisingpeaks at approximately 6.21, 12.91, and 16.32 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately12.32 and 19.09 degrees 2θ. In one embodiment, the solid form comprisespeaks at approximately positions 66.21, 6.47, 9.94, 12.32, 12.91, 16.32,16.64, 17.73, 19.09, 19.78, 19.88, 21.32, 24.60, 25.89, 26.00, and 27.54degrees 2θ.

In some embodiments, provided herein is a solid form comprising a hemiD-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 23.

Representative thermal characteristics of the hemi D-tartrate salt areprovided in FIG. 24A and FIG. 24B. A representative differentialscanning calorimetry (DSC) thermogram is presented in FIG. 24A. In someembodiments, provided herein is a solid form comprising a hemiD-tartrate salt of Compound (I-S) that exhibits a thermal event, ascharacterized by DSC, with a peak temperature of about 111° C., or witha peak temperature of about 169° C. In some embodiments, provided hereinis a solid form comprising a hemi D-tartrate salt of Compound (I-S) thatexhibits thermal events, as characterized by DSC, with a peaktemperature of about 111° C., and with a peak temperature of about 169°C. In some embodiments, provided herein is a solid form comprising ahemi D-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by a DSC thermogram which matches the DSC thermogrampresented in FIG. 24A.

A representative thermal gravimetric analysis curve of the hemiD-tartrate salt is provided in FIG. 24B, which exhibits a weight loss ofabout 4.60% of the total sample weight upon heating from about 20 toabout 150° C. In some embodiments, provided herein is a solid formcomprising a hemi D-tartrate salt of Compound (I-S), wherein the solidform is characterized by a TGA thermogram which matches the TGAthermogram presented in FIG. 24B.

A representative ¹H-NMR spectrum of the hemi D-tartrate salt is providedin FIG. 25. In some embodiments, provided herein is a solid formcomprising a hemi-D-tartrate salt of Compound (I-S), wherein the solidform is characterized by a ¹H-NMR spectrum which matches the ¹H-NMRspectrum presented in FIG. 25.

(viii) L-Tartrate

Provided herein is a solid form comprising a L-tartrate salt of Compound(I-S).

In some embodiments, the solid form is obtained by heating a mixture ofCompound (I-S) with L-tartaric acid and solvent. In some embodiments,the solvent in 2-propanol. In some embodiments, the mixture is heated toabout 50° C. In some embodiments, the solid form is isolated byfiltration.

In some embodiments, the molar ratio of Compound (I-S) to L-tartaricacid is approximately 1:1.

Without being limited by any particular theory, in some embodiments, thetartrate has the following formula:

A representative XRPD pattern of the tartrate is provided in FIG. 26.

In some embodiments, provided herein is a solid form comprising aL-tartrate salt of Compound (I-S) characterized by XRPD peaks located at1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or all of the following orapproximately the following positions 6.27, 7.21, 10.90, 11.97, 14.41,15.32, 17.08, 17.75, 18.79, 20.82, 23.40, and 25.28 degrees 2θ. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 9 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising aL-tartrate salt of Compound (I-S) having an XRPD pattern comprisingpeaks at approximately 6.27, 10.90, and 15.32 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately11.97, 14.41, and 17.08 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately positions 6.27, 7.21, 10.90, 11.97,14.41, 15.32, 17.08, 17.75, 18.79, 20.82, 23.40, and 25.28 degrees 2θ.

In some embodiments, provided herein is a solid form comprising aL-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 26.

Representative thermal characteristics of the L-tartrate salt areprovided in FIG. 27A and FIG. 27B. A representative differentialscanning calorimetry (DSC) thermogram is presented in FIG. 27A. In someembodiments, provided herein is a solid form comprising a L-tartratesalt of Compound (I-S) that exhibits a thermal event, as characterizedby DSC, with a peak temperature of about 114° C., or with a peaktemperature of about 123° C. In some embodiments, provided herein is asolid form comprising a L-tartrate salt of Compound (I-S) that exhibitsthermal events, as characterized by DSC, with a peak temperature ofabout 114° C., and with a peak temperature of about 123° C. In someembodiments, provided herein is a solid form comprising a L-tartratesalt of Compound (I-S), wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 27A.

A representative thermal gravimetric analysis curve of the L-tartratesalt is provided in FIG. 27B, which exhibits a weight loss of about3.76% of the total sample weight upon heating from about 25 to about125° C. In some embodiments, provided herein is a solid form comprisinga L-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by a TGA thermogram which matches the TGA thermogrampresented in FIG. 27B.

A representative ¹H-NMR spectrum of the L-tartrate salt is provided inFIG. 28. In some embodiments, provided herein is a solid form comprisinga L-tartrate salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 28.

(ix) Tosylate

Provided herein is a solid form comprising a tosylate salt of Compound(I-S).

In some embodiments, the solid form is obtained by heating a mixture ofCompound (I-S), solvent, and p-toluenesulfonic acid hydrate. In someembodiments, the solvent is acetonitrile. In some embodiments, the solidform is obtained by the steps of (1) heating a mixture of acetonitrile,Compound (I-S), and p-toluenesulfonic acid hydrate to 70° C. for about1.5 hr; (2) subsequently maintaining a temperature of about 50° C. forabout 5 hr; and (3) finally maintaining a temperature of about 20° C.for about 15 hr. In some embodiments, the solid form is isolated byfiltration.

In some embodiments, the molar ratio of Compound (I-S) top-toluenesulfonic acid in the solid form is approximately 2:1 to 1:2. Insome embodiments, the molar ratio is approximately 1:1.

Without being limited by any particular theory, in some embodiments, thebesylate has the following formula:

A representative XRPD pattern of the tosylate of Compound (I-S) isprovided in FIG. 29.

In some embodiments, provided herein is a solid form comprising atosylate salt of Compound (I-S) characterized by XRPD peaks located at1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or all ofthe following or approximately the following positions 7.41, 9.22, 9.77,15.41, 18.70, 18.84, 19.25, 20.66, 20.89, 21.98, 22.37, 22.97, 23.83,24.36, 24.89, 25.29, 25.55, 27.69, and 28.08 degrees 2θ. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 9 of the peaks. In someembodiments, the solid form is characterized by 11 of the peaks. In someembodiments, the solid form is characterized by 13 of the peaks. In someembodiments, the solid form is characterized by 15 of the peaks. In someembodiments, the solid form is characterized by 17 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising tosylateof Compound (I-S) having an XRPD pattern comprising peaks atapproximately 9.77, 15.41, and 19.25 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 7.41 and 22.97degrees 2θ. In one embodiment, the solid form comprises peaks atapproximately 77.41, 9.22, 9.77, 15.41, 18.70, 18.84, 19.25, 20.66,20.89, 21.98, 22.37, 22.97, 23.83, 24.36, 24.89, 25.29, 25.55, 27.69,and 28.08 degrees 2θ.

In some embodiments, provided herein is a solid form comprising atosylate salt of Compound (I-S), wherein the solid form is characterizedby an XRPD diffraction pattern which matches the XRPD pattern presentedin FIG. 29.

Representative thermal characteristics of the tosylate salt are providedin FIG. 30A and FIG. 30B. A representative differential scanningcalorimetry (DSC) thermogram is presented in FIG. 30A. In someembodiments, provided herein is a solid form comprising a tosylate saltof Compound (I-S) that exhibits a thermal event, as characterized byDSC, with a peak temperature of about 242° C. and an onset temperatureof about 237° C. In some embodiments, provided herein is a solid formcomprising a tosylate salt of Compound (I-S), wherein the solid form ischaracterized by a DSC thermogram which matches the DSC thermogrampresented in FIG. 30A.

A representative thermal gravimetric analysis curve of the tosylate saltis provided in FIG. 30B, which exhibits no substantial change of thetotal sample weight upon heating from about 25 to about 150° C. In someembodiments, provided herein is a solid form comprising a tosylate saltof Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 30B.

A representative ¹H-NMR spectrum of the tosylate salt is provided inFIG. 31. In some embodiments, provided herein is a solid form comprisinga tosylate salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 31.

(x) (+) Camphorsulfonic Acid

Provided herein is a solid form comprising a (+) camphorsulfonic acidsalt of Compound (I-S).

In some embodiments, the solid form is obtained by heating a mixture ofCompound (I-S), solvent, and (+) camphorsulfonate.

In some embodiments, the solvent is ethyl acetate. In some embodiments,the solid form is obtained by the steps of (1) heating a mixture ofCompound (II), (+) camphorsulfonate, and ethyl acetate to reflux forabout 28 hours and removing water. In some embodiments, water is removedvia Dean stark apparatus.

In some embodiments, the molar ratio of Compound (I-S) to (+)camphorsulfonic acid in the solid form is approximately 2:1 to 1:2. Insome embodiments, the molar ratio is approximately 1:1.

Without being limited by any particular theory, in some embodiments, the(+) camphorsulfonic acid salt has the following formula:

A representative XRPD pattern of the (+) camphorsulfonic acid salt ofCompound (I-S) is provided in FIG. 32.

In some embodiments, provided herein is a solid form comprising a (+)camphorsulfonic acid salt of Compound (I-S) characterized by XRPD peakslocated at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all ofthe following or approximately the following positions 5.61, 9.05,11.12, 13.97, 14.61, 15.34, 16.12, 16.35, 16.82, 17.20, 17.52, 18.67,20.92, 21.53, 26.40, and 27.34 degrees 2θ. In some embodiments, thesolid form is characterized by 3 of the peaks. In some embodiments, thesolid form is characterized by 5 of the peaks. In some embodiments, thesolid form is characterized by 7 of the peaks. In some embodiments, thesolid form is characterized by 9 of the peaks. In some embodiments, thesolid form is characterized by 11 of the peaks. In some embodiments, thesolid form is characterized by 13 of the peaks. In some embodiments, thesolid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising (+)camphorsulfonic acid salt of Compound (I-S) having an XRPD patterncomprising peaks at approximately 9.05, 14.61, and 16.82 degrees 2θ. Incertain embodiments, the solid form further comprises peaks atapproximately 13.97, 15.34, and 16.35 degrees 2θ. In one embodiment, thesolid form comprises peaks at approximately 5.61, 9.05, 11.12, 13.97,14.61, 15.34, 16.12, 16.35, 16.82, 17.20, 17.52, 18.67, 20.92, 21.53,26.40, and 27.34 degrees 2θ.

In some embodiments, provided herein is a solid form comprising a (+)camphorsulfonic acid salt of Compound (I-S), wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 32.

Representative thermal characteristics of the (+) camphorsulfonic acidsalt are provided in FIG. 33 and FIG. 34. A representative differentialscanning calorimetry (DSC) thermogram is presented in FIG. 33. In someembodiments, provided herein is a solid form of a (+) camphorsulfonicacid salt of Compound (I-S) that exhibits a thermal event, ascharacterized by DSC, with a peak temperature of about 195° C. and anonset temperature of about 181° C., or with a peak temperature of about251° C. In some embodiments, provided herein is a solid form of a (+)camphorsulfonic acid salt of Compound (I-S) that exhibits thermalevents, as characterized by DSC, with a peak temperature of about 195°C. and an onset temperature of about 181° C., and with a peaktemperature of about 251° C. In some embodiments, provided herein is asolid form comprising a (+) camphorsulfonic acid salt of Compound (I-S),wherein the solid form is characterized by a DSC thermogram whichmatches the DSC thermogram presented in FIG. 33.

A representative thermal gravimetric analysis curve of the (+)camphorsulfonic acid salt of Compound (I-S) is provided in FIG. 34,which exhibits a weight loss of about 1.79% of the total sample weightupon heating from about 25 to about 150° C. In some embodiments,provided herein is a solid form comprising a (+) camphorsulfonic acidsalt of Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 34.

A representative ¹H-NMR spectrum of the (+) camphorsulfonic acid salt ofCompound (I-S) is provided in FIG. 35. In some embodiments, providedherein is a solid form comprising a (+) camphorsulfonic acid salt ofCompound (I-S), wherein the solid form is characterized by a ¹H-NMRspectrum which matches the ¹H-NMR spectrum presented in FIG. 35.

5.2 Various Solid Forms of Compound (I-S) HCl Salt and Syntheses Thereof

Provided herein are solid forms of the HCl salt of Compound (I-S). Insome embodiments, the solid forms are crystalline. In some embodiments,the solid form is a hydrate, anhydrate, or solvate. Certain solid formof the HCl salt of Compound (I-S) have been described above.

Provided herein are various polymorphic forms of the HCl salt ofCompound (I-S).

(i) Form A

Provided herein is the Form A crystal form of the HCl salt of Compound(I-S).

A representative XRPD pattern of Form A is provided in FIG. 36. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all of thefollowing or approximately the following positions: 9.69, 12.82, 15.09,15.94, 16.76, 17.65, 19.44, 19.80, 22.30, 22.47, 22.95, 23.02, 24.29,24.48, 24.70, 26.27, 26.77, 27.60, 29.43, 29.72, and 32.91 degrees 2θ.In some embodiments, the solid form is characterized by 3 of the peaks.In some embodiments, the solid form is characterized by 5 of the peaks.In some embodiments, the solid form is characterized by 7 of the peaks.In some embodiments, the solid form is characterized by 10 of the peaks.In some embodiments, the solid form is characterized by 13 of the peaks.In some embodiments, the solid form is characterized by 15 of the peaks.In some embodiments, the solid form is characterized by all of thepeaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 15.09, 15.94, and 22.30 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately17.65, 22.47, and 26.77 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 9.69, 12.82, 15.09, 15.94, 16.76,17.65, 19.44, 19.80, 22.30, 22.47, 22.95, 23.02, 24.29, 24.48, 24.70,26.27, 26.77, 27.60, 29.43, 29.72, and 32.91 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 36.

In some embodiments, the Form A crystal form has an irregular rodcrystal habit. A representative crystal habit is presented in FIG. 37.

Representative thermal characteristics of the Form A crystal form of theHCl salt of Compound (I-S) are shown in FIG. 38 and FIG. 39. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 38. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 261° C.and an onset temperature of about 256° C. Without being limited by anyparticular theory, the event corresponds to melting and/ordecomposition. In some embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a DSC thermogram which matches the DSC thermogrampresented in FIG. 38.

A representative thermal gravimetric analysis curve of Form A isprovided in FIG. 39, which exhibits a weight loss of about 0.16% of thetotal sample weight upon heating from about 25 to about 120° C. Incertain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 39.

A representative ¹H-NMR spectrum of the Form A crystal form is presentedin FIG. 40. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 40.

A representative DVS isotherm plot is provided in FIG. 41. In certainembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S), wherein the solid form is characterized by a DVSisotherm plot which matches the DVS isotherm plot presented in FIG. 41.In some embodiments, a mass change of about 1.8% occurs between arelative humidity (RH) between 0% and 95%. Representative XRPD patternsof the Form A crystal form before and after it undergoesadsorption/desorption cycles are presented in FIG. 42. In oneembodiment, the Form A crystal remains as the Form A crystal after itundergoes adsorption/desorption cycles.

In some embodiments, the Form A crystal form remains as the Form Acrystal form after application of 2000-psi for about 1 minute. Arepresentative XRPD pattern of Form A after application of 2000-psi forabout 1 minute is presented in FIG. 43. In one embodiment, the Form Acrystal form remains as the Form A crystal form after application of2000-psi for about 1 minute.

In some embodiments, the Form A crystal form is an anhydrate.

Further properties of the Form A crystal form are provided in theExamples section.

(ii) Form B

Provided herein is the Form B crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form B crystal form is obtained byrecrystallization of a Form A crystal form in MeOH.

A representative XRPD pattern of Form B is provided in FIG. 44. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15 or all of the following or approximatelythe following positions: 7.11, 7.87, 9.93, 11.48, 13.90, 14.20, 15.71,20.71, 20.96, 21.36, 23.61, 26.68, 27.69, 27.76, 28.05, and 31.63degrees 2θ. In some embodiments, the solid form is characterized by 3 ofthe peaks. In some embodiments, the solid form is characterized by 5 ofthe peaks. In some embodiments, the solid form is characterized by 7 ofthe peaks. In some embodiments, the solid form is characterized by 10 ofthe peaks. In some embodiments, the solid form is characterized by 13 ofthe peaks. In some embodiments, the solid form is characterized by allof the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 7.11, 14.20, and 20.71 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 9.93 and 21.36degrees 2θ. In one embodiment, the solid form comprises peaks atapproximately 7.11, 7.87, 9.93, 11.48, 13.90, 14.20, 15.71, 20.71,20.96, 21.36, 23.61, 26.68, 27.69, 27.76, 28.05, and 31.63 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 44.

In some embodiments, the Form B crystal form has an irregular rodcrystal habit. A representative crystal habit is presented in FIG. 45.

Representative thermal characteristics of the Form B crystal form of theHCl salt of Compound (I-S) are shown in FIG. 46 and FIG. 47. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 46. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 174° C.and an onset temperature of about 170° C., or with a peak temperature ofabout 250° C. In some embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S) that exhibits thermal events, ascharacterized by DSC, with a peak temperature of about 174° C. and anonset temperature of about 170° C., and with a peak temperature of about250° C. Without being limited by any particular theory, the event with apeak temperature of about 174° C. corresponds to melting, and the eventwith a peak temperature of about 250° C. corresponds to decomposition.In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 46.

A representative thermal gravimetric analysis curve of Form B isprovided in FIG. 47, which exhibits a weight loss of about 7.60% of thetotal sample weight upon heating from about 25 to about 125° C. Incertain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 47.Without being limited by any particular theory, the weight losscorresponds to a loss of water and/or solvent.

A representative ¹H-NMR spectrum of the Form B crystal form is presentedin FIG. 48. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 48.

In some embodiments, the Form B crystal form is a hydrate of the HClsalt of Compound (I-S).

In some embodiments, the Form B crystal form exhibits the XRPDdiffraction pattern presented in FIG. 49 after being subjected toambient storage. In one embodiment, the Form B crystal form converts tothe Form A crystal form after being subjected to ambient storage.

Further properties of the Form B crystal form are provided in theExamples section.

(iii) Form C

Provided herein is the Form C crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form C crystal form is obtained byrecrystallization of a HCl salt of Compound (I-S) in DMSO/n-BuOH,DMSO/MTBE, or DMSO BuOAC.

A representative XRPD pattern of Form C is provided in FIG. 50. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, or all of the following or approximately the following positions:6.55, 7.65, 9.09, 13.14, 13.37, 19.62, 19.80, 22.40, and 23.32 degrees2θ. In some embodiments, the solid form is characterized by 3 of thepeaks. In some embodiments, the solid form is characterized by 5 of thepeaks. In some embodiments, the solid form is characterized by 7 of thepeaks. In some embodiments, the solid form is characterized by all ofthe peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 6.55, 13.14, and 13.37 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 9.09, 19.62, and19.80 degrees 2θ. In one embodiment, the solid form comprises peaks atapproximately 6.55, 7.65, 9.09, 13.14, 13.37, 19.62, 19.80, 22.40, and23.32 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 50.

In some embodiments, the Form C crystal form has an irregular crystalhabit. A representative crystal habit is presented in FIG. 51.

Representative thermal characteristics of the Form C crystal form of theHCl salt of Compound (I-S) are shown in FIG. 52 and FIG. 53. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 52. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 142°C., with a peak temperature of about 147° C., or with an onsettemperature of about 252° C. In some embodiments, provided herein is asolid form comprising a HCl salt of Compound (I-S) that exhibits thermalevents, as characterized by DSC, with a peak temperature of about 142°C., with a peak temperature of about 147° C., and with an onsettemperature of about 252° C. Without being limited by any particulartheory, the event with an onset temperature of about 252° C. correspondsto melting and/or decomposition. In certain embodiments, provided hereinis a solid form comprising a HCl salt of Compound (I-S), wherein thesolid form is characterized by a DSC thermogram which matches the DSCthermogram presented in FIG. 52.

A representative thermal gravimetric analysis curve of Form C isprovided in FIG. 53, which exhibits a weight loss of 1.55% of the totalsample weight upon heating from about 30 to about 80° C., and a weightloss of 15.14% of the total sample weight upon heating from about 80 toabout 175° C. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a TGA thermogram which matches the TGA thermogrampresented in FIG. 53. Without being limited by any particular theory,the weight loss corresponds to a loss of water and/or solvent.

In some embodiments, the Form C crystal form exhibits the XRPDdiffraction pattern presented in FIG. 54 after being subjected toheating to 165° C. In one embodiment, the Form C crystal form convertsto the Form A crystal form after being subjected to heating at 165° C.

A representative ¹H-NMR spectrum of the Form C crystal form is presentedin FIG. 55. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 55.

In some embodiments, the Form C crystal form is a DMSO solvate of theHCl salt of Compound (I-S).

In some embodiments, the Form C crystal form converts to the Form Acrystal form upon exposure to high humidity, e.g., higher than 70% RH,e.g., in a DVS instrument. Representative XRPD diffraction patterns ofthe Form C crystal form before and after exposure to high humidity in aDVS instrument are presented in FIG. 56.

Further properties of the Form C crystal form are provided in theExamples section.

(iv) Form D

Provided herein is the Form D crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form D crystal form is obtained byequilibration of Form A in MeCN/water (95:5).

A representative XRPD pattern of Form D is provided in FIG. 57. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following orapproximately the following positions: 6.82, 8.07, 9.56, 12.23, 13.52,14.16, 14.82, 15.71, 18.61, 18.85, 20.27, 21.65, 22.06, 25.00, 25.99,27.93, and 28.62 degrees 2θ. In some embodiments, the solid form ischaracterized by 3 of the peaks. In some embodiments, the solid form ischaracterized by 5 of the peaks. In some embodiments, the solid form ischaracterized by 7 of the peaks. In some embodiments, the solid form ischaracterized by 10 of the peaks. In some embodiments, the solid form ischaracterized by 13 of the peaks. In some embodiments, the solid form ischaracterized by 15 of the peaks. In some embodiments, the solid form ischaracterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 13.52, 14.16, and 25.00 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately6.82, 8.07, and 15.71 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 6.82, 8.07, 9.56, 12.23, 13.52, 14.16,14.82, 15.71, 18.61, 18.85, 20.27, 21.65, 22.06, 25.00, 25.99, 27.93,and 28.62 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 57.

In some embodiments, the Form D crystal form has an irregular crystalhabit. A representative crystal habit is presented in FIG. 58.

Representative thermal characteristics of the Form D crystal form of theHCl salt of Compound (I-S) are shown in FIG. 59 and FIG. 60. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 59. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 60° C.,with a peak temperature of about 169° C., or with a peak temperature ofabout 252° C. In some embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S) that exhibits thermal events, ascharacterized by DSC, with a peak temperature of about 60° C., with apeak temperature of about 169° C., and with a peak temperature of about252° C. Without being limited by any particular theory, the thermalevent with a peak temperature of about 60° C. corresponds to waterand/or solvent loss, the thermal event with a peak temperature of about169° C. corresponds to melting, and the thermal event with a peaktemperature of about 252° C. corresponds to decomposition. In certainembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S), wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 59.

A representative thermal gravimetric analysis curve of Form D isprovided in FIG. 60, which exhibits a weight loss of about 9.19% of thetotal sample weight upon heating from about 25 to about 125° C. Incertain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 60.Without being limited by any particular theory, the weight losscorresponds to a loss of water and/or solvent.

A representative ¹H-NMR spectrum of the Form D crystal form is presentedin FIG. 61. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 61.

A representative DVS isotherm plot is provided in FIG. 62. In certainembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S), wherein the solid form is characterized by a DVSisotherm plot which matches the DVS isotherm plot presented in FIG. 62.In some embodiments, a mass change of about 11% relative to dry massoccurs between a relative humidity (RH) between 50% and 80%, and a masschange of about 12% between 80-90% relative humidity during absorption.Without being limited by any particular theory, the mass change between80-90% RH corresponds to transformation of the solid form.

Representative XRPD patterns of the Form D crystal form before and afterit undergoes adsorption/desorption cycles are presented in FIG. 63. Inone embodiment, the Form D crystal form converts to the Form F crystalform after it undergoes adsorption/desorption cycles.

In some embodiments, the Form D crystal form is a hydrate of the HClsalt of Compound (I-S).

Further properties of the Form D crystal form are provided in theExamples section.

(v) Form E

Provided herein is the Form E crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form E crystal form is obtained by heating amixture of Compound (I-S), HCl, water, and acetonitrile at about 45° C.,followed by cooling. In some embodiments, the Form E crystal form isobtained by a method comprising the steps of: (1) heating a mixture ofCompound (I-S), acetonitrile, and water at about 45° C.; (2) adding HClto the mixture; (3) cooling the mixture to about room temperature toinduce precipitation; (4) reheating the mixture to about 45° C.; and (4)cooling the mixture to about room temperature. In certain embodiments,the Form E crystal form is isolated by filtration.

A representative XRPD pattern of Form E is provided in FIG. 64. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or all of the following or approximately the followingpositions: 8.48, 9.82, 13.27, 13.64, 16.05, 17.06, 17.73, 21.96, 25.71,26.15, and 28.03 degrees 2θ. In some embodiments, the solid form ischaracterized by 3 of the peaks. In some embodiments, the solid form ischaracterized by 5 of the peaks. In some embodiments, the solid form ischaracterized by 7 of the peaks. In some embodiments, the solid form ischaracterized by 9 of the peaks. In some embodiments, the solid form ischaracterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 9.82, 17.06, and 17.73 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 16.05, 25.71,and 26.15 degrees 2θ. In one embodiment, the solid form comprises peaksat approximately 8.48, 9.82, 13.27, 13.64, 16.05, 17.06, 17.73, 21.96,25.71, 26.15, and 28.03 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 64.

In some embodiments, the Form E crystal form has an irregular crystalhabit. A representative crystal habit is presented in FIG. 65.

Representative thermal characteristics of the Form E crystal form of theHCl salt of Compound (I-S) are shown in FIG. 66 and FIG. 67. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 66. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 111°C., with a peak temperature of about 185° C., or with a peak temperatureof about 250° C. In some embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S) that exhibits thermal events, ascharacterized by DSC, with a peak temperature of about 111° C., with apeak temperature of about 185° C., and with a peak temperature of about250° C. Without being limited by any particular theory, the event with apeak temperature of about 250° C. corresponds to melting and/ordecomposition. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a DSC thermogram which matches the DSC thermogrampresented in FIG. 66.

A representative thermal gravimetric analysis curve of Form E isprovided in FIG. 67, which exhibits a weight loss of about 4.49% uponheating from about 25 to about 120° C. Without being limited by anyparticular theory, in some embodiments, the weight loss corresponds to aKarl Fischer result showing a 4.2 wt % of water. In certain embodiments,provided herein is a solid form comprising a HCl salt of Compound (I-S),wherein the solid form is characterized by a TGA thermogram whichmatches the TGA thermogram presented in FIG. 67.

A representative ¹H-NMR spectrum of the Form E crystal form is presentedin FIG. 68. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 68.

A representative DVS isotherm plot is provided in FIG. 69. In certainembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S), wherein the solid form is characterized by a DVSisotherm plot which matches the DVS isotherm plot presented in FIG. 69.In some embodiments, a mass change of about 14% relative to dry massoccurs between a relative humidity (RH) between 50% and 80%. In someembodiments, a mass change is observed between 80-90% relative humidityduring absorption. Without being limited by any particular theory, themass change between 80-90% RH corresponds to transformation of the solidform.

Representative XRPD patterns of the Form E crystal form before and afterit undergoes adsorption/desorption cycles are presented in FIG. 70. Inone embodiment, the Form E crystal form converts to the Form F crystalform after it undergoes adsorption/desorption cycles.

In some embodiments, the Form E crystal form converts to Form A in anIPA slurry. In some embodiments, the Form E crystal form converts toForm F in IPA/water mixtures.

A representative XRPD pattern of the Form E crystal form taken after itis heated to 120° C. is presented in FIG. 71. In one embodiment, theForm E crystal form remains as the Form E crystal form after it isheated to 120° C. A representative XRPD pattern of Form E after it isheated to 190° C. is presented in FIG. 72. In one embodiment, the Form Ecrystal form converts to an amorphous form after it is heated to 190° C.

In some embodiments, the Form E crystal form is a hydrate.

Further properties of the Form E crystal form are provided in theExamples section.

(vi) Form F

Provided herein is the Form F crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form F crystal form is obtained by heating amixture of Compound (I-S), HCl, water, and 2-propanol at about 40° C.,followed by cooling and crystallization. In some embodiments,crystallization is induced by addition of 2-propanol. In certainembodiments, the Form F crystal form is isolated by filtration. In someembodiments, the Form F crystal form is obtained by slurrying Form E inan IPA/water mixture.

A representative XRPD pattern of Form F is provided in FIG. 73. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or all of the following or approximately the followingpositions: 7.10, 13.71, 14.22, 14.94, 16.35, 19.56, 20.87, 27.55, 28.36,30.10, and 34.81 degrees 2θ. In some embodiments, the solid form ischaracterized by 3 of the peaks. In some embodiments, the solid form ischaracterized by 5 of the peaks. In some embodiments, the solid form ischaracterized by 7 of the peaks. In some embodiments, the solid form ischaracterized by 9 of the peaks. In some embodiments, the solid form ischaracterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 13.71, 14.22, and 20.87 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately7.10, 16.35, and 28.36 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 7.10, 13.71, 14.22, 14.94, 16.35,19.56, 20.87, 27.55, 28.36, 30.10, and 34.81 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 73.

In some embodiments, the Form F crystal form has an irregular rodcrystal habit. A representative crystal habit is presented in FIG. 74.

Representative thermal characteristics of the Form F crystal form of theHCl salt of Compound (I-S) are shown in FIG. 75 and FIG. 76. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 75. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 83° C.and an onset temperature of about 63° C., with a peak temperature ofabout 217° C. and an onset temperature of about 204° C., or with a peaktemperature of about 250° C. In some embodiments, provided herein is asolid form comprising a HCl salt of Compound (I-S) that exhibits thermalevents, as characterized by DSC, with a peak temperature of about 83° C.and an onset temperature of about 63° C., with a peak temperature ofabout 217° C. and an onset temperature of about 204° C., and with a peaktemperature of about 250° C. In certain embodiments, provided herein isa solid form comprising a HCl salt of Compound (I-S), wherein the solidform is characterized by a DSC thermogram which matches the DSCthermogram presented in FIG. 75.

A representative thermal gravimetric analysis curve of Form F isprovided in FIG. 76, which exhibits a weight loss of 5.00% of the totalsample weight upon heating from about 30 to about 110° C. Without beinglimited by any particular theory, in some embodiments, the weight losscorresponds to a Karl Fischer result showing a 5.3 wt % of water. Incertain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 76.

A representative ¹H-NMR spectrum of the Form F crystal form is presentedin FIG. 77. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 77.

A representative DVS isotherm plot is provided in FIG. 78. In certainembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S), wherein the solid form is characterized by a DVSisotherm plot which matches the DVS isotherm plot presented in FIG. 78.In some embodiments, a mass change of about 6.3% relative to dry massoccurs between a relative humidity (RH) between 0% and 90%. In someembodiments, water content is stabilized between 5.2 and 6.3 wt % from10 to 90% was determined by DVS, which, in certain embodiments,corresponds to approximately 1.5-1.9 molar equivalents of water.

Representative XRPD patterns of the Form F crystal form before and afterit undergoes adsorption/desorption cycles are presented in FIG. 79. Inone embodiment, the Form F crystal form remains as the Form F crystalform after it undergoes adsorption/desorption cycles.

In some embodiments, the Form F crystal form converts to Form A when inIPA slurry.

A representative XRPD pattern of the Form F crystal form taken after itis heated to 120° C. is presented in FIG. 80. A representative TGApattern of the Form F crystal form taken after it is heated to 120° C.is presented in FIG. 81. In one embodiment, the Form F crystal formremains as the Form F crystal form after it is heated to 120° C.

In some embodiments, the Form F crystal form is a hydrate. In someembodiments, the Form F crystal form is a sesqui hydrate.

Further properties of the Form F crystal form are provided in theExamples section.

(vii) Form G

Provided herein is the Form G crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form G crystal form is obtained byrecrystallization of Form A in MeOH/MTBE.

A representative XRPD pattern of Form G is provided in FIG. 82. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15 or all of the following or approximatelythe following positions: 6.85, 7.81, 9.56, 11.59, 13.69, 16.30, 19.05,20.20, 20.60, 23.25, 23.57, 25.26, 26.81, 26.99, 27.51, and 31.57degrees 2θ. In some embodiments, the solid form is characterized by 3 ofthe peaks. In some embodiments, the solid form is characterized by 5 ofthe peaks. In some embodiments, the solid form is characterized by 7 ofthe peaks. In some embodiments, the solid form is characterized by 10 ofthe peaks. In some embodiments, the solid form is characterized by 13 ofthe peaks. In some embodiments, the solid form is characterized by allof the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 6.85, 20.20, and 20.60 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 9.56, 13.69,19.05, and 23.57 degrees 2θ. In one embodiment, the solid form comprisespeaks at approximately 6.85, 7.81, 9.56, 11.59, 13.69, 16.30, 19.05,20.20, 20.60, 23.25, 23.57, 25.26, 26.81, 26.99, 27.51, and 31.57degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 82.

Representative thermal characteristics of the Form G crystal form of theHCl salt of Compound (I-S) are shown in FIG. 83 and FIG. 84. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 83. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 199° C.and an onset temperature of about 185° C., or with a peak temperature ofabout 248° C. and an onset temperature of about 222° C. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) that exhibits thermal events, as characterized by DSC,with a peak temperature of about 199° C. and an onset temperature ofabout 185° C., and with a peak temperature of about 248° C. and an onsettemperature of about 222° C. In certain embodiments, provided herein isa solid form comprising a HCl salt of Compound (I-S), wherein the solidform is characterized by a DSC thermogram which matches the DSCthermogram presented in FIG. 83.

A representative thermal gravimetric analysis curve of Form G isprovided in FIG. 84, which exhibits a weight loss of about 1.92% of thetotal sample weight upon heating from about 30 to about 110° C., and aweight loss of about 12.27% of the total sample weight upon heating fromabout 110 to about 210° C. Without being limited by any particulartheory, in some embodiments, the weight loss of about 1.92% correspondsto a loss of water and or solvent, and the weight loss of 12.27%corresponds to desolvation. In certain embodiments, provided herein is asolid form comprising a HCl salt of Compound (I-S), wherein the solidform is characterized by a TGA thermogram which matches the TGAthermogram presented in FIG. 84.

A representative ¹H-NMR spectrum of the Form G crystal form is presentedin FIG. 85. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the ¹H-NMR spectrumpresented in FIG. 85.

In some embodiments, the Form G crystal form is a solvate. In someembodiments, the Form G crystal form is a MTBE solvate. In certainembodiments, the solvate contains about 0.5 molar equivalents of MTBErelative to Compound (I-S).

Further properties of the Form G crystal form are provided in theExamples section.

(viii) Form H

Provided herein is the Form H crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form H crystal form is obtained byrecrystallization of Form A in MeOH/toluene.

A representative XRPD pattern of Form H is provided in FIG. 86. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8 or all of the following or approximately the following positions:6.83, 9.47, 13.63, 16.13, 20.19, 20.58, 25.08, 26.99, and 27.55 degrees2θ. In some embodiments, the solid form is characterized by 3 of thepeaks. In some embodiments, the solid form is characterized by 5 of thepeaks. In some embodiments, the solid form is characterized by 7 of thepeaks. In some embodiments, the solid form is characterized by all ofthe peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 6.83, 20.19, and 20.58 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 9.47 and 13.63degrees 2θ. In one embodiment, the solid form comprises peaks atapproximately 6.83, 9.47, 13.63, 16.13, 20.19, 20.58, 25.08, 26.99, and27.55 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 86.

Representative thermal characteristics of the Form H crystal form of theHCl salt of Compound (I-S) are shown in FIG. 87 and FIG. 88. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 87. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 187°C., or with a peak temperature of about 255° C. In some embodiments,provided herein is a solid form comprising a HCl salt of Compound (I-S)that exhibits thermal events, as characterized by DSC, with a peaktemperature of about 187° C., and with a peak temperature of about 255°C. In certain embodiments, provided herein is a solid form comprising aHCl salt of Compound (I-S), wherein the solid form is characterized by aDSC thermogram which matches the DSC thermogram presented in FIG. 87.

A representative thermal gravimetric analysis curve of Form H isprovided in FIG. 88, which exhibits a weight loss of about 0.33% of thetotal sample weight upon heating from about 25 to about 80° C., and aweight loss of about 15.30% of the total sample weight upon heating fromabout 80 to about 200° C. Without being limited by any particulartheory, the weight loss of 15.30% corresponds to desolvation. In certainembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 88.

A representative ¹H-NMR spectrum of the Form H crystal form is presentedin FIG. 89. In certain embodiments, provided herein is a solid formcomprising a HCl salt of Compound (I-S), wherein the solid form ischaracterized by a ¹H-NMR spectrum which matches the 41-NMR spectrumpresented in FIG. 89.

In some embodiments, the Form H crystal form is a solvate. In someembodiments, the Form G crystal form is a toluene solvate.

Further properties of the Form H crystal form are provided in theExamples section.

(ix) Form I

Provided herein is the Form I crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form I crystal form is obtained byrecrystallization of Form A in DMSO/MeCN or DMSO/acetone.

A representative XRPD pattern of Form I is provided in FIG. 90. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5 orall of the following or approximately the following positions: 13.29,13.51, 13.95, 23.39, 24.10, and 24.30 degrees 2θ. In some embodiments,the solid form is characterized by 3 of the peaks. In some embodiments,the solid form is characterized by 5 of the peaks. In some embodiments,the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 13.95, 23.39, and 24.10 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately13.51 and 24.30 degrees 2θ. In one embodiment, the solid form comprisespeaks at approximately 13.29, 13.51, 13.95, 23.39, 24.10, and 24.30degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 90.

In some embodiments, the Form I crystal form exhibits the XRPD patternpresented in FIG. 91 after being washed with MeOAc. In one embodiment,the Form I crystal converts to the Form A crystal after being washedwith MeOAc.

In some embodiments, the Form I crystal form is a solvate.

Further properties of the Form I crystal form are provided in theExamples section.

(x) Form J

Provided herein is the Form J crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form J crystal form is obtained byrecrystallization of Form A in DMSO/THF.

A representative XRPD pattern of Form J is provided in FIG. 92. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all of the followingor approximately the following positions: 4.86, 6.66, 7.08, 8.22, 9.65,9.82, 11.70, 13.26, 13.48, 15.11, 16.39, 18.12, 20.06, 20.39, 20.51,21.20, 22.15, 22.72, 23.45, and 24.15 degrees 2θ. In some embodiments,the solid form is characterized by 3 of the peaks. In some embodiments,the solid form is characterized by 5 of the peaks. In some embodiments,the solid form is characterized by 7 of the peaks. In some embodiments,the solid form is characterized by 10 of the peaks. In some embodiments,the solid form is characterized by 13 of the peaks. In some embodiments,the solid form is characterized by 15 of the peaks. In some embodiments,the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 4.86, 13.48, and 20.06 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 20.39, 22.15,and 23.45 degrees 2θ. In one embodiment, the solid form comprises peaksat approximately 4.86, 6.66, 7.08, 8.22, 9.65, 9.82, 11.70, 13.26,13.48, 15.11, 16.39, 18.12, 20.06, 20.39, 20.51, 21.20, 22.15, 22.72,23.45, and 24.15 degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 92.

Representative thermal characteristics of the Form J crystal form of theHCl salt of Compound (I-S) are shown in FIG. 93 and FIG. 94. Arepresentative differential scanning calorimetry (DSC) thermogram ispresented in FIG. 93. In some embodiments, provided herein is a solidform comprising a HCl salt of Compound (I-S) that exhibits a thermalevent, as characterized by DSC, with a peak temperature of about 70° C.,with a peak temperature of about 106° C., with a peak temperature ofabout 127° C., or with an onset temperature of about 251° C. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) that exhibits thermal events, as characterized by DSC,with a peak temperature of about 70° C., with a peak temperature ofabout 106° C., with a peak temperature of about 127° C., and with anonset temperature of about 251° C. In certain embodiments, providedherein is a solid form comprising a HCl salt of Compound (I-S), whereinthe solid form is characterized by a DSC thermogram which matches theDSC thermogram presented in FIG. 93.

A representative thermal gravimetric analysis curve of Form J isprovided in FIG. 94, which exhibits a weight loss of about 4.73% of thetotal sample weight upon heating from about 25 to about 80° C., a weightloss of about 7.59% of the total sample weight upon heating from about80 to about 120° C., and a weight loss of about 10.21% of the totalsample weight upon heating from about 120 to about 200° C. Without beinglimited by any particular theory, the weight loss of about 4.73%corresponds to loss of water and/or solvent, the weight loss of about7.59% and the weight loss of about 10.21% correspond to desolvation. Incertain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 94

In some embodiments, the Form J crystal form is a solvate.

Further properties of the Form J crystal form are provided in theExamples section.

(xi) Form K

Provided herein is the Form K crystal form of the HCl salt of Compound(I-S).

In some embodiments, the Form K crystal form is obtained by drying FormF at about 0% relative humidity. In one embodiment, the drying isperformed by placing Form F in a chamber containing drierite for about16 hours.

A representative XRPD pattern of Form K is provided in FIG. 95. In someembodiments, provided herein is a solid form comprising a HCl salt ofCompound (I-S) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6,7 or all of the following or approximately the following positions:7.09, 9.35, 14.03, 14.22, 14.76, 15.91, 19.17, and 21.60 degrees 2θ. Insome embodiments, the solid form is characterized by 3 of the peaks. Insome embodiments, the solid form is characterized by 5 of the peaks. Insome embodiments, the solid form is characterized by 7 of the peaks. Insome embodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S) having an XRPD pattern comprising peaks atapproximately 7.09, 14.03, and 14.22 degrees 2θ. In certain embodiments,the solid form further comprises peaks at approximately 9.35 and 21.60degrees 2θ. In one embodiment, the solid form comprises peaks atapproximately 7.09, 9.35, 14.03, 14.22, 14.76, 15.91, 19.17, and 21.60degrees 2θ.

In certain embodiments, provided herein is a solid form comprising a HClsalt of Compound (I-S), wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD diffraction patternpresented in FIG. 95.

A representative XRPD pattern of Form K after it is exposed to ambientconditions is provided in FIG. 96. In one embodiment, the Form K crystalconverts to the Form F crystal after it is exposed to ambient condition.

Further properties of the Form K crystal form are provided in theExamples section.

(xii) Interconversion of HCl Forms

The interconversion of Form A-K is depicted in FIG. 106.

5.3 Salts and Solid Forms of Racemic Compound (I) and Syntheses Thereof

Provided herein are salts of racemic Compound (I). In some embodiments,racemic Compound (I) is a salt of H-X, wherein X is F, Cl, Br, I, RSO₃,or RCO₂, wherein R is alkyl, aryl, substituted alkyl, or substitutedaryl. In some embodiments, the salt is a hydrochloric acid salt. Withoutbeing limited by any particular theory, the acids are associated withthe basic nitrogen of the nitrogen on the morpholine ring of racemicCompound (I).

Also provided herein are solid forms of racemic Compound (I) and ofsalts of racemic Compound (I). In some embodiments, the solid form is ananhydrate, hydrate, or solvate. In some embodiments, the solvate is amethanol solvate.

(i) Freebase Anhydrate

Provided herein is an anhydrate of racemic Compound (I). In someembodiments, the anhydrate is obtained by heating a mixture of racemicCompound (I) and acetonitrile. In some embodiments, the anhydrate isobtained by heating a mixture of racemic Compound (I) and acetonitrileto about 40° C. and subsequently cooling the mixture to about roomtemperature. In some embodiments, the anhydrate is obtained by heating amixture of racemic Compound (I) and acetonitrile to about 40° C.,subsequently cooling the mixture to about room temperature, andisolating the anhydrate by filtration.

Without being limited by any particular theory, in some embodiments, theanhydrate has the following formula:

A representative XRPD pattern of the anhydrate of racemic Compound (I)is provided in FIG. 97.

In some embodiments, provided herein is a solid form comprising racemicCompound (I) characterized by XRPD peaks located at 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or all of the following orapproximately the following positions: 4.95, 7.11, 8.96, 9.97, 12.67,14.30, 14.83, 16.20, 19.26, 20.09, 20.61, 21.81, 22.82, 23.21, 23.58,24.37, 26.57, 27.09, and 32.16 degrees 2θ. In some embodiments, thesolid form is characterized by 3 of the peaks. In some embodiments, thesolid form is characterized by 5 of the peaks. In some embodiments, thesolid form is characterized by 7 of the peaks. In some embodiments, thesolid form is characterized by 10 of the peaks. In some embodiments, thesolid form is characterized by 13 of the peaks. In some embodiments, thesolid form is characterized by 15 of the peaks. In some embodiments, thesolid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising racemicCompound (I) having an XRPD pattern comprising peaks at approximately4.95, 8.96, and 14.83 degrees 2θ. In certain embodiments, the solid formfurther comprises peaks at approximately 12.67, 14.30, 20.09, and 26.57degrees 2θ. In some embodiments, the solid form comprises peaks at 4.95,7.11, 8.96, 9.97, 12.67, 14.30, 14.83, 16.20, 19.26, 20.09, 20.61,21.81, 22.82, 23.21, 23.58, 24.37, 26.57, 27.09, and 32.16 degrees 2θ.

In some embodiments, provided herein is a solid form comprising racemicCompound (I), wherein the solid form is characterized by an XRPDdiffraction pattern which matches the XRPD pattern presented in FIG. 97.

Representative thermal characteristics of the anhydrate are provided inFIG. 98A and FIG. 98B. A representative differential scanningcalorimetry (DSC) thermogram is presented in FIG. 98A. In someembodiments, provided herein is a solid form comprising racemic Compound(I) that exhibits a thermal event, as characterized by DSC, with a peaktemperature of about 217° C. and an onset temperature of about 216° C.In certain embodiments, the event corresponds to melting. In someembodiments, provided herein is a solid form comprising racemic Compound(I), wherein the solid form is characterized by a DSC thermogram whichmatches the DSC thermogram presented in FIG. 98A.

A representative thermal gravimetric analysis curve of the anhydrate isprovided in FIG. 98B, which exhibits no substantial change of the totalsample weight upon heating from about 25 to about 200° C. In someembodiments, provided herein is a solid form comprising racemic Compound(I), wherein the solid form is characterized by a TGA thermogram whichmatches the TGA thermogram presented in FIG. 98B.

(ii) Freebase Hydrate

Provided herein is a hydrate of racemic Compound (I). In someembodiments, the hydrate is obtained by heating a mixture of racemicCompound (I), acetonitrile, and water. In some embodiments, the hydrateis obtained by heating a mixture of racemic Compound (I), acetonitrile,and water to about 40° C. and subsequently cooling the mixture to aboutroom temperature. In some embodiments, the hydrate is obtained byheating a mixture of racemic Compound (I), acetonitrile, and water toabout 40° C., subsequently cooling the mixture to about roomtemperature, and isolating the hydrate by filtration. In someembodiments, the volume ratio of acetonitrile to water used in thepreparation of the hydrate is about 1:1. In some embodiments, thehydrate has a molar ratio of racemic Compound (I) to water ofapproximately 2:1 to 1:2. In some embodiments, the hydrate has a molarratio of racemic Compound (I) to water of approximately 1:1.

Without being limited by any particular theory, in some embodiments, thehydrate has the following formula:

A representative XRPD pattern of the hydrate of racemic Compound (I) isprovided in FIG. 99.

In some embodiments, provided herein is a solid form comprising racemicCompound (I) and water characterized by XRPD peaks located at 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or all of the following orapproximately the following positions: 8.34, 8.95, 11.79, 12.88, 14.01,16.02, 17.01, 17.28, 18.00, 20.46, 23.05, 24.37, 25.71, 26.21, 26.38,and 27.37 degrees 2θ. In some embodiments, the solid form ischaracterized by 3 of the peaks. In some embodiments, the solid form ischaracterized by 5 of the peaks. In some embodiments, the solid form ischaracterized by 7 of the peaks. In some embodiments, the solid form ischaracterized by 10 of the peaks. In some embodiments, the solid form ischaracterized by 13 of the peaks. In some embodiments, the solid form ischaracterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising racemicCompound (I) and water having an XRPD pattern comprising peaks atapproximately 14.01, 17.28, and 26.21 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately8.34, 11.79, and 17.01 degrees 2θ. In some embodiments, the solid formcomprises peaks at 8.34, 8.95, 11.79, 12.88, 14.01, 16.02, 17.01, 17.28,18.00, 20.46, 23.05, 24.37, 25.71, 26.21, 26.38, and 27.37 degrees 2θ.

In some embodiments, provided herein is a solid form comprising racemicCompound (I) and water, wherein the solid form is characterized by anXRPD diffraction pattern which matches the XRPD pattern presented inFIG. 99.

Representative thermal characteristics of the hydrate are provided inFIG. 100A and FIG. 100B. A representative differential scanningcalorimetry (DSC) thermogram is presented in FIG. 100A. In someembodiments, provided herein is a solid form comprising racemic Compound(I) and water that exhibits a thermal event, as characterized by DSC,with a peak temperature of about 94° C., with a peak temperature ofabout 137° C. and an onset temperature of about 128° C., with a peaktemperature of about 157° C. and an onset temperature of about 149° C.,or with a peak temperature of about 218° C. and an onset temperature ofabout 215° C. In some embodiments, provided herein is a solid formcomprising racemic Compound (I) and water that exhibits thermal events,as characterized by DSC, with a peak temperature of about 94° C., with apeak temperature of about 137° C. and an onset temperature of about 128°C., with a peak temperature of about 157° C. and an onset temperature ofabout 149° C., and with a peak temperature of about 218° C. and an onsettemperature of about 215° C. Without being limited by any particulartheory, the event with a peak temperature of about 94° C. corresponds tomelting, the event with an onset temperature of about 149° C.corresponds to recrystallization, and the event with an onsettemperature of about 215° C. corresponds to melting. In someembodiments, provided herein is a solid form comprising racemic Compound(I) and water, wherein the solid form is characterized by a DSCthermogram which matches the DSC thermogram presented in FIG. 100A.

A representative thermal gravimetric analysis curve of the hydrate isprovided in FIG. 100B, which exhibits a weight loss of about 4.90% ofthe total sample weight upon heating from about 25 to about 125° C. Insome embodiments, provided herein is a solid form comprising racemicCompound (I) and water, wherein the solid form is characterized by a TGAthermogram which matches the TGA thermogram presented in FIG. 100B.

(iii) Hydrochloride Hydrates

Provided herein is a hydrate of the hydrochloride salt of racemicCompound (I). Provided herein is a solid form comprising a hydrochloridesalt of racemic Compound (I) and water. In some embodiments, the solidform is obtained by heating a mixture of a hydrochloride salt of racemicCompound (I), isopropanol, and water. In some embodiments, the solidform is obtained by heating a mixture of a hydrochloride salt of racemicCompound (I), isopropanol, and water to about 50° C., and subsequentlycooling the mixture to about room temperature. In some embodiments, thesolid form is obtained by heating a mixture of a hydrochloride salt ofracemic Compound (I), isopropanol, and water to about 50° C.,subsequently cooling the mixture to about room temperature, andisolating the solid form by filtration. In some embodiments, the volumeratio of isopropanol to water used in the preparation of the solid formis about 4:1. In some embodiments, the solid form has a molar ratio ofracemic Compound (I) to HCl of approximately 2:1 to 1:2. In someembodiments, the solid form has a molar ratio of racemic Compound (I) toHCl of approximately 1:1. In some embodiments, the solid form has amolar ratio of racemic Compound (I) to water of approximately 2:1 to1:2. In some embodiments, the solid form has a molar ratio of racemicCompound (I) to water of approximately 1:1.

Without being limited by any particular theory, in some embodiments, thehydrochloride salt hydrate has the following formula:

A representative XRPD pattern of a hydrate HCl salt of racemic Compound(I) is provided in FIG. 101.

In some embodiments, provided herein is a solid form comprising a HClsalt of racemic Compound (I) and water characterized by XRPD peakslocated at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of the following orapproximately the following positions: 5.17, 7.17, 9.84, 13.88, 14.30,15.36, 16.42, 19.82, 20.48, 21.22, 25.74, and 26.95 degrees 2θ. In someembodiments, the solid form is characterized by 3 of the peaks. In someembodiments, the solid form is characterized by 5 of the peaks. In someembodiments, the solid form is characterized by 7 of the peaks. In someembodiments, the solid form is characterized by 10 of the peaks. In someembodiments, the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of racemic Compound (I) and water having an XRPD pattern comprisingpeaks at approximately 13.88, 14.30, and 15.36 degrees 2θ. In certainembodiments, the solid form further comprises peaks at approximately9.84, 16.42, and 19.82 degrees 2θ. In one embodiment, the solid formcomprises peaks at approximately 5.17, 7.17, 9.84, 13.88, 14.30, 15.36,16.42, 19.82, 20.48, 21.22, 25.74, and 26.95 degrees 2θ.

In some embodiments, provided herein is a solid form comprising a HClsalt of racemic Compound (I) and water, wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 101.

Representative thermal characteristics of the hydrate are provided inFIG. 102A and FIG. 102B. A representative differential scanningcalorimetry (DSC) thermogram is presented in FIG. 102A. In someembodiments, provided herein is a solid form comprising a HCl salt ofracemic Compound (I) and water that exhibits a thermal event, ascharacterized by DSC, with a peak temperature of about 122° C., or witha peak temperature of about 255° C. and an onset temperature of about252° C. In some embodiments, provided herein is a solid form comprisinga HCl salt of racemic Compound (I) and water that exhibits thermalevents, as characterized by DSC, with a peak temperature of about 122°C., and with a peak temperature of about 255° C. and an onsettemperature of about 252° C. Without being limited by any particulartheory, the event with an onset temperature of about 252° C. correspondsto melting/decomposition. In some embodiments, provided herein is asolid form comprising a HCl salt of racemic Compound (I) and water,wherein the solid form is characterized by a DSC thermogram whichmatches the DSC thermogram presented in FIG. 102A.

A representative thermal gravimetric analysis curve of the hydrate ofthe HCl salt of racemic Compound (I) is provided in FIG. 102B, whichexhibits a weight loss of about 4.27% of the total sample weight uponheating from about 25 to about 100° C. In some embodiments, providedherein is a solid form comprising a HCl salt of racemic Compound (I) andwater, wherein the solid form is characterized by a TGA thermogram whichmatches the TGA thermogram presented in FIG. 102B.

A representative DVS isotherm plot of the hydrate of the HCl salt ofracemic Compound (I) is provided in FIG. 103. In some embodiments,provided herein is a solid form comprising a HCl salt of racemicCompound (I) and water, wherein the solid form is characterized by a DVSisotherm plot which matches the DVS isotherm plot presented in FIG. 103.

(iv) Hydrochloride MeOH Solvate

Provided herein is a MeOH solvate of the hydrochloride salt of racemicCompound (I). Provided herein is a solid form comprising a hydrochloridesalt of racemic Compound (I) and MeOH. In some embodiments, the solidform is obtained by heating a mixture of a hydrochloride salt of racemicCompound (I) and methanol. In some embodiments, the solid form isobtained by heating a mixture of a hydrochloride salt of racemicCompound (I) and methanol to about 50° C., and subsequently cooling themixture to about room temperature. In some embodiments, the solid formis obtained by heating a mixture of a hydrochloride salt of racemicCompound (I) and methanol to about 50° C., subsequently cooling themixture to about room temperature, and isolating the solid form byfiltration. In some embodiments, the methanol used in the preparation ofthe solid form is pre-dried on 3-A molecular sieves. In someembodiments, the solid form has a molar ratio of racemic Compound (I) toHCl of approximately 2:1 to 1:2. In some embodiments, the solid form hasa molar ratio of racemic Compound (I) to HCl of approximately 1:1. Insome embodiments, the solid form has a molar ratio of racemic Compound(I) to methanol of approximately 2:1 to 1:2. In some embodiments, thesolid form has a molar ratio of racemic Compound (I) to methanol ofapproximately 1:1.

Without being limited by any particular theory, in some embodiments, thehydrochloride salt hydrate has the following formula:

A representative XRPD pattern of a MeOH solvate of HCl salt of racemicCompound (I) is provided in FIG. 104.

In some embodiments, provided herein is a solid form comprising a HClsalt of racemic Compound (I) and methanol characterized by XRPD peakslocated at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or allof the following or approximately the following positions: 7.73, 10.45,12.38, 14.54, 15.06, 16.18, 18.95, 20.00, 21.26, 21.97, 22.24, 22.30,22.61, 24.17, 26.10, 26.86, and 30.13 degrees 2θ. In some embodiments,the solid form is characterized by 3 of the peaks. In some embodiments,the solid form is characterized by 5 of the peaks. In some embodiments,the solid form is characterized by 7 of the peaks. In some embodiments,the solid form is characterized by 10 of the peaks. In some embodiments,the solid form is characterized by 13 of the peaks. In some embodiments,the solid form is characterized by all of the peaks.

In some embodiments, provided herein is a solid form comprising a HClsalt of racemic Compound (I) and methanol having an XRPD patterncomprising peaks at approximately 12.38, 14.54, and 26.10 degrees 2θ. Incertain embodiments, the solid form further comprises peaks atapproximately 15.06, 20.00, and 26.86 degrees 2θ. In one embodiment, thesolid form comprises peaks at approximately 7.73, 10.45, 12.38, 14.54,15.06, 16.18, 18.95, 20.00, 21.26, 21.97, 22.24, 22.30, 22.61, 24.17,26.10, 26.86, and 30.13 degrees 2θ.

In some embodiments, provided herein is a solid form comprising a HClsalt of racemic Compound (I) and methanol, wherein the solid form ischaracterized by an XRPD diffraction pattern which matches the XRPDpattern presented in FIG. 104.

In one embodiment, a MeOH solvate of HCl salt of racemic Compound (I)converts to a hydrate of HCl salt of racemic Compound (I) upon exposureto ambient moisture.

5.4 Methods of Treatment, Prevention, and Management

Provided herein are methods of treating, preventing, and/or managingvarious diseases or disorders using a solid form of Compound (I), a saltof Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases,immunodeficiency disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder.

As used herein, unless otherwise specified, the term “preventing” refersto the treatment with or administration of a compound provided herein,with or without other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of cancer and/or otherdisorders described herein. The term “prevention” includes theinhibition or reduction of a symptom of the particular disease. Patientswith familial history of a disease in particular are candidates forpreventive regimens in certain embodiments. In addition, patients whohave a history of recurring symptoms are also potential candidates forthe prevention. In this regard, the term “prevention” may beinterchangeably used with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. In certain cases, the beneficial effects that asubject derives from a prophylactic or therapeutic agent do not resultin a cure of the disease or disorder.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to inhibit orreduce a symptom of a disease or to prevent recurrence of a disease. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the inhibition or reduction of asymptom of a disease or recurrence of a disease. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

In one embodiment, provided herein is a method of treating andpreventing cancer, which comprises administering to a patient a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof.

In another embodiment, provided herein is method of managing cancer,which comprises administering to a patient a solid form of Compound (I),a salt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof.

Also provided herein are methods of treating patients who have beenpreviously treated for cancer but are non-responsive to standardtherapies, as well as those who have not previously been treated. Theinvention also encompasses methods of treating patients regardless ofpatient's age, although some diseases or disorders are more common incertain age groups. The invention further encompasses methods oftreating patients who have undergone surgery in an attempt to treat thedisease or condition at issue, as well as those who have not. Becausepatients with cancer have heterogeneous clinical manifestations andvarying clinical outcomes, the treatment given to a patient may vary,depending on his/her prognosis. The skilled clinician will be able toreadily determine without undue experimentation specific secondaryagents, types of surgery, and types of non-drug based standard therapythat can be effectively used to treat an individual patient with cancer.

As used herein, the term “cancer” includes, but is not limited to, solidtumors and blood born tumors. Specific examples of cancer include, butare not limited to, cancers of skin (e.g., melanoma); lymph node;breast; cervix; uterus; gastrointestinal tract; lung; ovary; prostate;colon; rectum; mouth; brain; head and neck; throat; testes; kidney;pancreas; bone; spleen; liver; bladder; larynx; nasal passages; andAIDS-related cancers. The compounds are also useful for treating cancersof the blood and bone marrow, such as multiple myeloma and acute andchronic leukemias, for example, lymphoblastic, myelogenous, lymphocytic,and myelocytic leukemias. The compounds provided herein can be used fortreating, preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unresectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistant to chemotherapy or radiation.

In certain embodiments, the cancer is a blood borne tumor. In certainembodiments, the blood borne tumor is metastatic. In certainembodiments, the blood borne tumor is drug resistant. In certainembodiments, the cancer is myeloma, leukemia or lymphoma.

In one embodiment, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference. In one embodiment, the canceris acute myelogenous leukemia or acute myeloid leukemia. In anotherembodiment, provided herein are methods of treating, preventing, and/ormanaging myeloid proliferative diseases or myeloid dysplastic syndromeusing a solid form of Compound (I), a salt of Compound (I), a solid formof a salt of Compound (I), or a stereoisomer thereof.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, provided herein are methods of treating,preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma (ILL),diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyticlymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mantle zonelymphoma). In one embodiment, the cancer is diffuse large B-Celllymphoma, follicular lymphoma, or mantle cell lymphoma. In oneembodiment, provided herein are methods for the treatment or managementof non-Hodgkin's lymphoma (NHL), including but not limited to, diffuselarge B-cell lymphoma (DLBCL), using prognostic factors.

In certain embodiments, the cancer is a solid tumor. In certainembodiments, the solid tumor is metastatic. In certain embodiments, thesolid tumor is drug-resistant. In certain embodiments, the solid tumoris hepatocellular carcinoma, prostate cancer, ovarian cancer, orglioblastoma.

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, keratoses andrelated symptoms, skin diseases or disorders characterized withovergrowths of the epidermis, scleroderma, cutaneous vasculitis, acne,and wrinkles.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-telangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, sepsis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

Also provided herein are methods of treating, preventing, and/ormanaging diseases, disorders and/or conditions associated withimmune-related and inflammatory diseases comprising administering atherapeutically effective amount of a solid form of Compound (I), a saltof Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof. In certain embodiments, the disease is selectedfrom lupus, scleroderma, Sjögren syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome and myasthenia gravis. In certainembodiments, the disease is scleroderma or lupus.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing scleroderma or a symptom thereof, comprisingadministering a therapeutically effective amount of a solid form ofCompound (I), a salt of Compound (I), a solid form of a salt of Compound(I), or a stereoisomer thereof, to a patient having scleroderma.

In certain embodiments, provided herein are methods of preventingscleroderma or a symptom thereof, comprising administering an effectiveamount of a solid form of Compound (I), a salt of Compound (I), a solidform of a salt of Compound (I), or a stereoisomer thereof, to a patientat risk of having scleroderma.

In certain embodiments, the scleroderma is localized, systemic, limitedor diffuse scleroderma.

In certain embodiments, the systemic scleroderma comprises CRESTsyndrome (Calcinosis, Raynaud's syndrome, esophagaeal dysfunction ordysmotility, sclerodactyly, telangiectasia). Scleroderma is also knownas systemic sclerosis or progressive systemic sclerosis. In certainembodiments, provided herein are methods of treating or preventingRaynaud's disease or syndrome. In certain embodiments, systemicsclerosis comprises scleroderma lung disease, scleroderma renal crisis,cardiac manifestations, muscular weakness (including fatigue or limitedCREST), gastrointestinal dysmotility and spasm, and abnormalities in thecentral, peripheral and autonomic nervous system (including carpaltunnel syndrome followed by trigeminal neuralgia). It also includesgeneral disability, including depression, and impact on quality of life.

In certain embodiments, limited scleroderma is limited to the hands, theface, neck, or combinations thereof.

In certain embodiments, diffuse scleroderma comprises skin tighteningand also occurs above the wrists (or elbows). In certain embodiments,the diffuse systemic sclerosis is sine scleroderma, comprising internalorgan fibrosis, but no skin tightening; or familial progressive systemicsclerosis.

In one embodiment, scleroderma is not associated with wasting, such asdisease-related wasting.

In one embodiment, provided herein are methods for the reduction,inhibition, or prevention of one or more of the following symptoms ofscleroderma: (i) gradual hardening, thickening, and tightening of theskin (e.g., in extremities, such as hands, face, and feet); (ii) skindiscoloration; (iii) numbness of extremities; (iv) shiny skin; (v) smallwhite lumps under the surface of the skin that erupt into a chalky whitefluid; (vi) Raynaud's esophagaeal dysfunction (pain, numbness, and/orcolor changes in the hands caused by spasm of the blood vessels uponexposure to cold or emotional stress); (vii) telangiectasia (red spotson, e.g., the hands, palms, forearms, face, and lips); (viii) painand/or stiffness of the joints; (ix) swelling of the hands and feet; (x)itching of the skin; (xi) stiffening and curling of the fingers; (xii)ulcers (sores) on the outside of certain joints, such as knuckles andelbows; (xiii) digestive problems, such as heartburn, difficulty inswallowing, diarrhea, irritable bowel, and constipation; (xiv) fatigueand weakness; (xv) shortness of breath; (xvi) arthritis; (xvii) hairloss; (xviii) internal organ problems; (xix) digital ulcers; or (xx)digital auto-amputation, comprising administering an effective amount ofa solid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, to a patient in needthereof.

Without being limited by any particular theory, it is believed that asolid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, enhances Th1 immuneresponse, and suppresses Th2 immune response, which may result inanti-fibrotic effects in the skin.

Further provided herein are methods for improving or reducing the skinthickness of a patient having scleroderma comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to the patient. In one embodiment, the skin thickness is reduced byabout 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about70% about 80%, about 90% or more.

Further provided herein are methods for achieving one or more clinicalendpoints associated with scleroderma comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to a patient in need thereof.

Further provided herein are methods for increasing the overall survival,objective response rate, time to progression, progression-free survivaland/or time-to-treatment failure of a patient having sclerodermacomprising administering an effective amount of a solid form of Compound(I), a salt of Compound (I), a solid form of a salt of Compound (I), ora stereoisomer thereof, to the patient.

Further provided herein are methods for decreasing mortality,respiratory mortality and/or respiratory hospitalization of a patienthaving scleroderma comprising administering an effective amount of asolid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, to the patient.

Further provided herein are methods for improving the modified Rodnanskin score of a patient having scleroderma comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to the patient. In one embodiment, the improvement in modified Rodnanskin score is 5, 10, 15 or 20 points or more.

Further provided herein are methods for improving or reducing the skinthickness of a patient having scleroderma comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to the patient. In one embodiment, the skin thickness is reduced byabout 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about70% about 80%, about 90% or more.

Further provided herein are methods for improving or reducing skininduration of a patient having scleroderma comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to the patient.

Further provided herein are methods for improving the dermatologyquality of life index of a patient having scleroderma comprisingadministering an effective amount of a solid form of Compound (I), asalt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof, to the patient.

Further provided herein are methods for improving the pulmonary functionof a patient having scleroderma comprising administering an effectiveamount of a solid form of Compound (I), a salt of Compound (I), a solidform of a salt of Compound (I), or a stereoisomer thereof, to thepatient.

Further provided herein are methods for improving the carbon monoxidediffusing capacity of a patient having scleroderma comprisingadministering an effective amount of a solid form of Compound (I), asalt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof, to the patient. In one embodiment, the carbonmonoxide diffusing capacity of a patient is improved by an improvementin the diffusing capacity of the lung for carbon monoxide (DLco) ofabout 10%, about 20%, about 25%, about 30%, about 40%, about 50%, about60%, about 70% about 80%, about 90% or more.

Further provided herein are methods for improving the Mahler Dyspneaindex of a patient having scleroderma comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to the patient. In one embodiment, the improvement in Mahler Dyspneaindex is 4, 5, 6, 7, 8, 9 or 10 points or more.

Further provided herein are methods for improving the Saint George'sRespiratory Questionnaire score of a patient having sclerodermacomprising administering an effective amount of a solid form of Compound(I), a salt of Compound (I), a solid form of a salt of Compound (I), ora stereoisomer thereof, to the patient. In one embodiment, theimprovement in Saint George's Respiratory Questionnaire score is 4, 8,12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 points or more.

Further provided herein are methods for improving the UCLA sclerodermaclinical trial consortium gastrointestinal tract score of a patienthaving scleroderma comprising administering an effective amount of asolid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, to the patient.

Further provided herein are methods for treating or preventing digitalulcer of a patient or patient population having scleroderma comprisingadministering an effective amount of a solid form of Compound (I), asalt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof, to the patient.

Further provided herein are methods improving flow-mediated dilatationof a patient having scleroderma comprising administering an effectiveamount of a solid form of Compound (I), a salt of Compound (I), a solidform of a salt of Compound (I), or a stereoisomer thereof, to thepatient.

Further provided herein are methods improving or increasing the sixminute walk distance of a patient having scleroderma comprisingadministering an effective amount of a solid form of Compound (I), asalt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof, to the patient. In one embodiment, the improvementin the six minute walk distance is about 200 meters, about 250 meters,about 300 meters, about 350 meters, about 400 meters or more.

In certain embodiments, provided herein are methods of treating,preventing, and/or managing lupus erythematosus or a symptom thereof,comprising administering a therapeutically effective amount of a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof, to a patient having lupuserythematosus.

In one embodiment, provided herein are methods of preventing lupuserythematosus or a symptom thereof, comprising administering aneffective amount of a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,to a patient at risk of having lupus erythematosus.

In certain embodiments, provided herein are methods for treating,preventing, and/or managing systemic lupus erythematosus (SLE),cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE),or drug-induced lupus.

The phrase “Systemic lupus erythematosus” is interchangeably used hereinwith SLE and lupus and refers to all manifestations of the disease asknown in the art (including remissions and flares). In SLE, abnormalhyperactivity of B lymphocytes and massive abnormal production ofimmunoglobulin gamma (IgG) auto-antibodies play a key role. Thispathological process results in sequestration and destruction ofIg-coated cells, fixation and cleaving of complement proteins, andrelease of chemotaxins, vasoactive peptides and destructive enzymes intotissues (Hahn B H. Systemic Lupus Erythematosus. In: Kasper D L,Braunwald E, Fauci A S, Hauser S L, Longo D L, Jameson, J L, editors.In: Harrison's Principles of Internal Medicine (16th edition). New York(US): McGraw-Hill; 2005. pp. 1960-196′7).

Symptoms of SLE vary from person to person, and may come and go. In mostpatients, the symptoms include joint pain and swelling. Frequentlyaffected joints are the fingers, hands, wrists, and knees. Some patientsdevelop arthritis. Other common symptoms include: chest pain when takinga deep breath, fatigue, fever with no other cause, general discomfort,uneasiness, or ill feeling (malaise), hair loss, mouth sores, swollenlymph nodes, sensitivity to sunlight, skin rash—a “butterfly” rash overthe cheeks and bridge of the nose affects about half of people with SLE,in some patients, the rash gets worse in sunlight, and the rash may alsobe widespread.

Other symptoms depend on what part of the body is affected, and mayinclude the following:

-   -   Brain and nervous system: headaches, numbness, tingling,        seizures, vision problems, personality changes,    -   Digestive tract: abdominal pain, nausea, and vomiting,    -   Heart: abnormal heart rhythms (arrhythmias),    -   Lung: coughing up blood and difficulty breathing, and    -   Skin: patchy skin color, fingers that change color when cold        (Raynaud's phenomenon).

Some patients only have skin symptoms. This is called discoid lupus.

In one embodiment, provided herein are methods of treating moderate,severe, or very severe SLE. The term “severe SLE” as used herein refersto an SLE condition where the patient has one or more severe orlife-threatening symptoms (such as hemolytic anemia, extensive heart orlung involvement, kidney disease, or central nervous systeminvolvement).

Further provided herein are methods for achieving one or more clinicalendpoints associated with SLE comprising administering an effectiveamount of a solid form of Compound (I), a salt of Compound (I), a solidform of a salt of Compound (I), or a stereoisomer thereof, to a patientin need thereof.

Further provided herein are methods for increasing the overall survival,objective response rate, time to progression, progression-free survivaland/or time-to-treatment failure of a patient having SLE comprisingadministering an effective amount of a solid form of Compound (I), asalt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof, to the patient.

In certain embodiment, a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,acts as an inhibitor of primary human memory CD19+ B-celldifferentiation to the plasmablast stage. Without being limited by anyparticular theory, it is believed that a solid form of Compound (I), asalt of Compound (I), a solid form of a salt of Compound (I), or astereoisomer thereof, blocks cells at a premature stage therebydecreasing the numbers of plasmablasts that are capable of producinghigh levels of immunoglobulin. A functional consequence of this effectis reduced immunoglobulin G (IgG) and immunoglobulin M (IgM) productionin these differentiation cultures.

In certain embodiments, a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,inhibits of the ability of primary human memory CD19+ B-cells todifferentiate to the plasmablast stage. In certain embodiments, a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof, has no significant effect onmature CD138+ plasma cells in short term cultures. In certainembodiments, a solid form of Compound (I), a salt of Compound (I), asolid form of a salt of Compound (I), or a stereoisomer thereof,inhibits B cell differentiation factors including interferon regulatoryfactor 4 (IRF4), lymphocyte-induced maturation protein (BLIMP),X-box-protein-1 (XBP-1) and B cell lymphoma 6 (Bc16).

Further provided herein are methods of treating, managing, or preventingother immune-related diseases or conditions using a solid form ofCompound (I), a salt of Compound (I), a solid form of a salt of Compound(I), or a stereoisomer thereof. In certain embodiments, for example,provided herein is a method of treating an individual having a diseaseor disorder, wherein the disease or disorder is caused by, or isassociated with, an inappropriate or undesirable immune response, e.g.,a disease, disorder or condition that can be treated beneficially byimmunosuppression, comprising administering to the individual a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof.

In various specific embodiments, said immune-related disease is one ormore of selected from Sjögren syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome, myasthenia gravis, Addison's disease,alopecia areata, ankylosing spondylitis, antiphospholipid antibodysyndrome, antiphospholipid syndrome (primary or secondary), asthma,autoimmune gastritis, autoimmune hemolytic anemia, autoimmune hepatitis,autoimmune inner ear disease, autoimmune lymphoproliferative disease,autoimmune thrombocytopenic purpura, Balo disease, Behcet's disease,bullous pemphigoid, cardiomyopathy, celiac disease, Chagas disease,chronic inflammatory demyelinating polyneuropathy, cicatrical pemphigoid(e.g., mucous membrane pemphigoid), cold agglutinin disease, degosdisease, dermatitis hepatiformis, essential mixed cryoglobulinemia,Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome,Hashimoto's thyroiditis (Hashimoto's disease; autoimmune thyroditis),idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura, IgAnephropathy, juvenile arthritis, lichen planus, Ménière disease, mixedconnective tissue disease, morephea, narcolepsy, neuromyotonia,pediatric autoimmune neuropsychiatric disorders (PANDAs), pemphigusvulgaris, pernicious anemia, polyarteritis nodosa, polychondritis,polymyalgia rheumatica, primary agammaglobulinemia, primary biliarycirrhosis, Raynaud disease (Raynaud phenomenon), Reiter's syndrome,relapsing polychondritis, rheumatic fever, Sjogren's syndrome,stiff-person syndrome (Moersch-Woltmann syndrome), Takayasu's arteritis,temporal arteritis (giant cell arteritis), uveitis, vasculitis (e.g.,vasculitis not associated with lupus erythematosus), vitiligo, and/orWegener's granulomatosis.

In other embodiments, provided herein is the use of the salts or solidforms in various immunological applications in combination with avaccination, for example, as vaccine adjuvant. Although any methods andmanners of use of the salts or solid forms provided herein incombination with a vaccine are contemplated herein, a non-limitingexample of such uses is the use of the salts or solid forms providedherein as vaccine adjuvants, according to the administration regimensdisclosed in U.S. Provisional Application No. 60/712,823, filed Sep. 1,2005, which is incorporated herein in its entirety by reference. Theseembodiments also relate to the uses of salts and solid forms providedherein in combination with vaccines to treat or prevent cancer orinfectious diseases, and other various uses of compounds providedherein, such as, but not limited to, reduction or desensitization ofallergic reactions.

Doses the salts or solid forms provided herein vary depending on factorssuch as: specific indication to be treated, prevented, or managed; ageand condition of a patient; and amount of second active agent used, ifany. In certain embodiments, a therapeutically or prophylacticallyeffective amount of the compound is from about 0.005 to about 1,000 mgper day, from about 0.01 to about 500 mg per day, from about 0.01 toabout 250 mg per day, from about 0.01 to about 100 mg per day, fromabout 0.1 to about 100 mg per day, from about 0.5 to about 100 mg perday, from about 1 to about 100 mg per day, from about 0.01 to about 50mg per day, from about 0.1 to about 50 mg per day, from about 0.5 toabout 50 mg per day, from about 1 to about 50 mg per day, from about0.02 to about 25 mg per day, or from about 0.05 to about 10 mg per day.

In certain embodiment, a therapeutically or prophylactically effectiveamount is from about 0.005 to about 1,000 mg per day, from about 0.01 toabout 500 mg per day, from about 0.01 to about 250 mg per day, fromabout 0.01 to about 100 mg per day, from about 0.1 to about 100 mg perday, from about 0.5 to about 100 mg per day, from about 1 to about 100mg per day, from about 0.01 to about 50 mg per day, from about 0.1 toabout 50 mg per day, from about 0.5 to about 50 mg per day, from about 1to about 50 mg per day, from about 0.02 to about 25 mg per day, or fromabout 0.05 to about 10 mg every other day.

In certain embodiments, the therapeutically or prophylacticallyeffective amount is about 0.1, about 0.2, about 0.5, about 1, about 2,about 5, about 10, about 15, about 20, about 25, about 30, about 40,about 45, about 50, about 60, about 70, about 80, about 90, about 100,or about 150 mg per day.

In one embodiment, the recommended daily dose range of a solid form ofCompound (I), a salt of Compound (I), a solid form of a salt of Compound(I), or a stereoisomer thereof, for the conditions described herein liewithin the range of from about 0.5 mg to about 50 mg per day, preferablygiven as a single once-a-day dose, or in divided doses throughout a day.In some embodiments, the dosage ranges from about 1 mg to about 50 mgper day. In other embodiments, the dosage ranges from about 0.5 to about5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

In a specific embodiment, the recommended starting dosage may be 0.5, 1,2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, therecommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. Thedose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In aspecific embodiment, the compound can be administered in an amount ofabout 25 mg/day to patients with NHL (e.g., DLBCL). In a particularembodiment, the compound can be administered in an amount of about 10mg/day to patients with NHL (e.g., DLBCL).

In certain embodiments, the therapeutically or prophylacticallyeffective amount is from about 0.001 to about 100 mg/kg/day, from about0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, fromabout 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day,0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, fromabout 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day,from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3mg/kg/day, from about 0.01 to about 2 mg/kg/day, or from about 0.01 toabout 1 mg/kg/day.

The administered dose can also be expressed in units other thanmg/kg/day. For example, doses for parenteral administration can beexpressed as mg/m²/day. One of ordinary skill in the art would readilyknow how to convert doses from mg/kg/day to mg/m²/day to given eitherthe height or weight of a subject or both (see,www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1mg/kg/day for a 65 kg human is approximately equal to 38 mg/m²/day.

In certain embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 0.001 to about 500 μM, about 0.002 to about200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, fromabout 1 to about 50 μM, about 0.02 to about 25 μM, from about 0.05 toabout 20 μM, from about 0.1 to about 20 μM, from about 0.5 to about 20μM, or from about 1 to about 20 μM.

In other embodiments, the amount of the compound administered issufficient to provide a plasma concentration of the compound at steadystate, ranging from about 5 to about 100 nM, about 5 to about 50 nM,about 10 to about 100 nM, about 10 to about 50 nM or from about 50 toabout 100 nM.

As used herein, the term “plasma concentration at steady state” is theconcentration reached after a period of administration of a solid formof Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof. Once steady state is reached,there are minor peaks and troughs on the time dependent curve of theplasma concentration of the compound.

In certain embodiments, the amount of the compound administered issufficient to provide a maximum plasma concentration (peakconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.02 to about 25 μM,from about 0.05 to about 20 μM, from about 0.1 to about 20 μM, fromabout 0.5 to about 20 μM, or from about 1 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide a minimum plasma concentration (troughconcentration) of the compound, ranging from about 0.001 to about 500μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01to about 50 μM, from about 1 to about 50 μM, about 0.01 to about 25 μM,from about 0.01 to about 20 μM, from about 0.02 to about 20 μM, fromabout 0.02 to about 20 μM, or from about 0.01 to about 20 μM.

In certain embodiments, the amount of the compound administered issufficient to provide an area under the curve (AUC) of the compound,ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 toabout 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, orfrom about 5,000 to about 10,000 ng*hr/mL.

In certain embodiments, the patient to be treated with one of themethods provided herein has not been treated with anticancer therapyprior to the administration of a solid form of Compound (I), a salt ofCompound (I), a solid form of a salt of Compound (I), or a stereoisomerthereof. In certain embodiments, the patient to be treated with one ofthe methods provided herein has been treated with anticancer therapyprior to the administration of a solid form of Compound (I), a salt ofCompound (I), a solid form of a salt of Compound (I), or a stereoisomerthereof. In certain embodiments, the patient to be treated with one ofthe methods provided herein has developed drug resistance to theanticancer therapy.

The methods provided herein encompass treating a patient regardless ofpatient's age, although some diseases or disorders are more common incertain age groups. Further provided herein is a method for treating apatient who has undergone surgery in an attempt to treat the disease orcondition at issue, as well in one who has not. Because the subjectswith cancer have heterogeneous clinical manifestations and varyingclinical outcomes, the treatment given to a particular subject may vary,depending on his/her prognosis. The skilled clinician will be able toreadily determine without undue experimentation, specific secondaryagents, types of surgery, and types of non-drug based standard therapythat can be effectively used to treat an individual subject with cancer.

Depending on the disease to be treated and the subject's condition, asolid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, may be administered byoral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,CIV, intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration. A solid form ofCompound (I), a salt of Compound (I), a solid form of a salt of Compound(I), or a stereoisomer thereof, may be formulated, alone or together, insuitable dosage unit with pharmaceutically acceptable excipients,carriers, adjuvants and vehicles, appropriate for each route ofadministration.

In one embodiment, a solid form of Compound (I), a salt of Compound (I),a solid form of a salt of Compound (I), or a stereoisomer thereof, isadministered orally. In another embodiment, a solid form of Compound(I), a salt of Compound (I), a solid form of a salt of Compound (I), ora stereoisomer thereof, is administered parenterally. In yet anotherembodiment, a solid form of Compound (I), a salt of Compound (I), asolid form of a salt of Compound (I), or a stereoisomer thereof, isadministered intravenously.

a solid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, can be delivered as asingle dose such as, e.g., a single bolus injection, or oral tablets orpills; or over time, such as, e.g., continuous infusion over time ordivided bolus doses over time. The compound can be administeredrepeatedly if necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205-216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or MM scan and other commonly accepted evaluation modalities.

a solid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, can be administeredonce daily (QD), or divided into multiple daily doses such as twicedaily (BID), three times daily (TID), and four times daily (QID). Inaddition, the administration can be continuous (i.e., daily forconsecutive days or every day), intermittent, e.g., in cycles (i.e.,including days, weeks, or months of rest without drug). As used herein,the term “daily” is intended to mean that a therapeutic compound isadministered once or more than once each day, for example, for a periodof time. The term “continuous” is intended to mean that a therapeuticcompound, is administered daily for an uninterrupted period of at least10 days to 52 weeks. The term “intermittent” or “intermittently” as usedherein is intended to mean stopping and starting at either regular orirregular intervals. For example, intermittent administration of a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof, is administration for one tosix days per week, administration in cycles (e.g., daily administrationfor two to eight consecutive weeks, then a rest period with noadministration for up to one week), or administration on alternate days.The term “cycling” as used herein is intended to mean that a therapeuticcompound, is administered daily or continuously but with a rest period.

In some embodiments, the frequency of administration is in the range ofabout a daily dose to about a monthly dose. In certain embodiments,administration is once a day, twice a day, three times a day, four timesa day, once every other day, twice a week, once every week, once everytwo weeks, once every three weeks, or once every four weeks. In oneembodiment, a solid form of Compound (I), a salt of Compound (I), asolid form of a salt of Compound (I), or a stereoisomer thereof, isadministered once a day. In another embodiment, a solid form of Compound(I), a salt of Compound (I), a solid form of a salt of Compound (I), ora stereoisomer thereof, is administered twice a day. In yet anotherembodiment, a solid form of Compound (I), a salt of Compound (I), asolid form of a salt of Compound (I), or a stereoisomer thereof, isadministered three times a day. In still another embodiment, a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof, is administered four times aday.

In certain embodiments, a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,is administered once per day from one day to six months, from one weekto three months, from one week to four weeks, from one week to threeweeks, or from one week to two weeks. In certain embodiments, a solidform of Compound (I), a salt of Compound (I), a solid form of a salt ofCompound (I), or a stereoisomer thereof, is administered once per dayfor one week, two weeks, three weeks, or four weeks. In one embodiment,a solid form of Compound (I), a salt of Compound (I), a solid form of asalt of Compound (I), or a stereoisomer thereof, is administered onceper day for one week. In another embodiment, a solid form of Compound(I), a salt of Compound (I), a solid form of a salt of Compound (I), ora stereoisomer thereof, is administered once per day for two weeks. Inyet another embodiment, a solid form of Compound (I), a salt of Compound(I), a solid form of a salt of Compound (I), or a stereoisomer thereof,is administered once per day for three weeks. In still anotherembodiment, a solid form of Compound (I), a salt of Compound (I), asolid form of a salt of Compound (I), or a stereoisomer thereof, isadministered once per day for four weeks.

5.5 Clinical Trials Endpoints for Cancer Approval

“Overall survival” is defined as the time from randomization until deathfrom any cause, and is measured in the intent-to-treat population.Overall survival should be evaluated in randomized controlled studies.Demonstration of a statistically significant improvement in overallsurvival can be considered to be clinically significant if the toxicityprofile is acceptable, and has often supported new drug approval.

Several endpoints are based on tumor assessments. These endpointsinclude disease free survival (DFS), objective response rate (ORR), timeto progression (TTP), progression-free survival (PFS), andtime-to-treatment failure (TTF). The collection and analysis of data onthese time-dependent endpoints are based on indirect assessments,calculations, and estimates (e.g., tumor measurements).

Generally, “disease free survival” (DFS) is defined as the time fromrandomization until recurrence of tumor or death from any cause.Although overall survival is a conventional endpoint for most adjuvantsettings, DFS can be an important endpoint in situations where survivalmay be prolonged, making a survival endpoint impractical. DFS can be asurrogate for clinical benefit or it can provide direct evidence ofclinical benefit. This determination is based on the magnitude of theeffect, its risk-benefit relationship, and the disease setting. Thedefinition of DFS can be complicated, particularly when deaths are notedwithout prior tumor progression documentation. These events can bescored either as disease recurrences or as censored events. Although allmethods for statistical analysis of deaths have some limitations,considering all deaths (deaths from all causes) as recurrences canminimize bias. DFS can be overestimated using this definition,especially in patients who die after a long period without observation.Bias can be introduced if the frequency of long-term follow-up visits isdissimilar between the study arms or if dropouts are not random becauseof toxicity.

“Objective response rate” (ORR) is defined as the proportion of patientswith tumor size reduction of a predefined amount and for a minimum timeperiod. Response duration usually is measured from the time of initialresponse until documented tumor progression. Generally, the FDA hasdefined ORR as the sum of partial responses plus complete responses.When defined in this manner, ORR is a direct measure of drug antitumoractivity, which can be evaluated in a single-arm study. If available,standardized criteria should be used to ascertain response. A variety ofresponse criteria have been considered appropriate (e.g., RECISTcriteria) (Therasse et al., (2000) J. Natl. Cancer Inst, 92: 205-16).The significance of ORR is assessed by its magnitude and duration, andthe percentage of complete responses (no detectable evidence of tumor).

“Time to progression” (TTP) and “progression-free survival” (PFS) haveserved as primary endpoints for drug approval. TTP is defined as thetime from randomization until objective tumor progression; TTP does notinclude deaths. PFS is defined as the time from randomization untilobjective tumor progression or death. Compared with TTP, PFS is thepreferred regulatory endpoint. PFS includes deaths and thus can be abetter correlate to overall survival. PFS assumes patient deaths arerandomly related to tumor progression. However, in situations where themajority of deaths are unrelated to cancer, TTP can be an acceptableendpoint.

As an endpoint to support drug approval, PFS can reflect tumor growthand be assessed before the determination of a survival benefit. Itsdetermination is not confounded by subsequent therapy. For a givensample size, the magnitude of effect on PFS can be larger than theeffect on overall survival. However, the formal validation of PFS as asurrogate for survival for the many different malignancies that existcan be difficult. Data are sometimes insufficient to allow a robustevaluation of the correlation between effects on survival and PFS.Cancer trials are often small, and proven survival benefits of existingdrugs are generally modest. The role of PFS as an endpoint to supportlicensing approval varies in different cancer settings. Whether animprovement in PFS represents a direct clinical benefit or a surrogatefor clinical benefit depends on the magnitude of the effect and therisk-benefit of the new treatment compared to available therapies.

“Time-to-treatment failure” (TTF) is defined as a composite endpointmeasuring time from randomization to discontinuation of treatment forany reason, including disease progression, treatment toxicity, anddeath. TTF is not recommended as a regulatory endpoint for drugapproval. TTF does not adequately distinguish efficacy from theseadditional variables. A regulatory endpoint should clearly distinguishthe efficacy of the drug from toxicity, patient or physician withdrawal,or patient intolerance.

5.6 Second Active Agents

A salt or solid form provided herein can be combined with otherpharmacologically active compounds (“second active agents”) in methodsand compositions provided herein. Certain combinations may worksynergistically in the treatment of particular types diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. Salt or solid form can also work to alleviate adverse effectsassociated with certain second active agents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetlyase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Omnitarg™)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin™)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);PI3K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

In certain embodiments, large molecule active agents are biologicalmolecules, such as naturally occurring or artificially made proteins.Proteins that are particularly useful in this disclosure includeproteins that stimulate the survival and/or proliferation ofhematopoietic precursor cells and immunologically active poietic cellsin vitro or in vivo. Others stimulate the division and differentiationof committed erythroid progenitors in cells in vitro or in vivo.Particular proteins include, but are not limited to: interleukins, suchas IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2),IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a,interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferonbeta-I a, and interferon gamma-I b; GM-CF and GM-CSF; GC-CSF, BCG,cancer antibodies, and EPO.

Particular proteins that can be used in the methods and compositions ofthe disclosure include, but are not limited to: filgrastim, which issold in the United States under the trade name NEUPOGEN® (Amgen,Thousand Oaks, Calif.); sargramostim, which is sold in the United Statesunder the trade name LEUKINE® (Immunex, Seattle, Wash.); and recombinantEPO, which is sold in the United States under the trade name EPGEN®(Amgen, Thousand Oaks, Calif.).

Inhibitors of ActRII receptors or activin-ActRII inhibitors may be usedin the methods and compositions provided herein. Inhibitors of ActRIIreceptors include ActRIIA inhibitors and ActRIIB inhibitors. Inhibitorsof ActRII receptors can be polypeptides comprising activin-bindingdomains of ActRII. In certain embodiments, the activin-binding domaincomprising polypeptides are linked to an Fc portion of an antibody(i.e., a conjugate comprising an activin-binding domain comprisingpolypeptide of an ActRII receptor and an Fc portion of an antibody isgenerated). In certain embodiments, the activin-binding domain is linkedto an Fc portion of an antibody via a linker, e.g., a peptide linker.Examples of such non-antibody proteins selected for activin or ActRIIAbinding and methods for design and selection of the same are found inWO/2002/088171, WO/2006/055689, WO/2002/032925, WO/2005/037989, US2003/0133939, and US 2005/0238646, each of which is incorporated hereinby reference in its entirety. In one embodiment, the inhibitor of ActRIIreceptors is ACE-11. In another embodiment, the inhibitor of ActRIIreceptors is ACE-536.

Recombinant and mutated forms of GM-CSF can be prepared as described inU.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; the disclosure ofeach of which is incorporated herein by reference in its entirety.Recombinant and mutated forms of G-CSF can be prepared as described inU.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; thedisclosure of each of which is incorporated herein by reference in itsentirety.

This disclosure encompasses the use of native, naturally occurring, andrecombinant proteins. The disclosure further encompasses mutants andderivatives (e.g., modified forms) of naturally occurring proteins thatexhibit, in vivo, at least some of the pharmacological activity of theproteins upon which they are based. Examples of mutants include, but arenot limited to, proteins that have one or more amino acid residues thatdiffer from the corresponding residues in the naturally occurring formsof the proteins. Also encompassed by the term “mutants” are proteinsthat lack carbohydrate moieties normally present in their naturallyoccurring forms (e.g., nonglycosylated forms). Examples of derivativesinclude, but are not limited to, pegylated derivatives and fusionproteins, such as proteins formed by fusing IgG1 or IgG3 to the proteinor active portion of the protein of interest. See, e.g., Penichet, M. L.and Morrison, S. L., J. Immunol. Methods 248:91-101 (2001).

Antibodies that can be used in combination with the compounds providedherein include monoclonal and polyclonal antibodies. Examples ofantibodies include, but are not limited to, trastuzumab (HERCEPTIN®),rituximab (RITUXAN®), bevacizumab (AVASTIN™), pertuzumab (OMNITARG™),tositumomab (BEXXAR®), edrecolomab (PANOREX®), panitumumab and G250. Thecompounds provided herein can also be combined with or used incombination with anti-TNF-α antibodies.

Large molecule active agents may be administered in the form ofanti-cancer vaccines. For example, vaccines that secrete, or cause thesecretion of, cytokines such as IL-2, SCF, CXC14 (platelet factor 4),G-CSF, and GM-CSF can be used in the methods, pharmaceuticalcompositions, and kits of the disclosure. See, e.g., Emens, L. A., etal., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

Second active agents that are small molecules can also be used toalleviate adverse effects associated with the administration of thecompounds provided herein. However, like some large molecules, many arebelieved to be capable of providing a synergistic effect whenadministered with (e.g., before, after or simultaneously) the compoundsprovided herein. Examples of small molecule second active agentsinclude, but are not limited to, anti-cancer agents, antibiotics,immunosuppressive agents, and steroids.

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; lapatinib (Tykerb®);abraxane; ace-11; acivicin; aclarubicin; acodazole hydrochloride;acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantroneacetate; amrubicin; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib(COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine;crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine;dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin;doxorubicin hydrochloride; droloxifene; droloxifene citrate;dromostanolone propionate; duazomycin; edatrexate; eflornithinehydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine;epirubicin hydrochloride; erbulozole; esorubicin hydrochloride;estramustine; estramustine phosphate sodium; etanidazole; etoposide;etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine;fenretinide; floxuridine; fludarabine phosphate; fluorouracil;flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabinehydrochloride; herceptin; hydroxyurea; idarubicin hydrochloride;ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecanhydrochloride; lanreotide acetate; lapatinib; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; romidepsin; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; stem cell treatments such asPDA-001; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalansodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevee), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB 1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

In one embodiment, the second active agent is proteasome inhibitor. Inone embodiment, the proteasome inhibitor is bortezomib, disulfiram,epigallocatechin-3-gallate, salinosporamide A, carfilzomib, ONX 0912,CEP-18770, or MLN9708.

In one embodiment, the second active agent is HDAC inhibitor. In oneembodiment, the HDAC inhibitor is vorinostat, romidepsin, panobinostat,valproic acid, belinostat, mocetinostat, abexinostat, entinostat, SB939,resminostat, givinostat, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202,CG200745, ACY-1215, sulforaphane, kevetrin, or trichostatin A.

In one embodiment, the second active agent is mitotic inhibitor. In oneembodiment, the mitotic inhibitor is taxanes, vinca alkaloids, orcolchicines. In one embodiment, the taxane is paclitaxel (Abraxane) ordocetaxel. In one embodiment, the vinca alkaloid is vinblastine,vincristine, vindesine, or vinorelbine.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228, and 2005/0143344; and U.S. provisional application No.60/631,870.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavir),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrer), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2a, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium, 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione, latanoprost(see U.S. Pat. No. 6,225,348), tetracycline and its derivatives,rifamycin and its derivatives, macrolides, metronidazole (U.S. Pat. Nos.6,218,369 and 6,015,803), genistein, genistin, 6′-O-Mal genistin,6′-O-Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O-Ac daidzin,glycitein, glycitin, 6′-O-Mal glycitin, biochanin A, formononetin (U.S.Pat. No. 6,001,368), triamcinolone acetomide, dexamethasone (U.S. Pat.No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. 5,632,984),basic fibroblast growth factor (bFGF), transforming growth factor b(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen activatorfactor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (EliLilly), Miravant, and RETISERT implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-a), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,a-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a salt or solid form provided herein and the secondactive agents to a patient can occur simultaneously or sequentially bythe same or different routes of administration. The suitability of aparticular route of administration employed for a particular activeagent will depend on the active agent itself (e.g., whether it can beadministered orally without decomposing prior to entering the bloodstream) and the disease being treated. One of administration forcompounds provided herein is oral. Routes of administration for thesecond active agents or ingredients are known to those of ordinary skillin the art. See, e.g., Physicians' Desk Reference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Salts and solid forms provided herein and otheractive ingredients can be administered to a patient prior to, during, orafter the occurrence of the adverse effect associated with conventionaltherapy.

5.7 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a salt or solid form provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a salt or solid formprovided herein is administered for a greater number of cycles thanwould typically cause dose-limiting toxicity in a patient to whom asecond active ingredient is not also being administered.

In one embodiment, a salt or solid form provided herein is administereddaily and continuously for three or four weeks at a dose of from about0.1 mg to about 500 mg per day, followed by a rest of one or two weeks.In other embodiments, the dose can be from about 1 mg to about 300 mg,from about 0.1 mg to about 150 mg, from about 1 mg to about 200 mg, fromabout 10 mg to about 100 mg, from about 0.1 mg to about 50 mg, fromabout 1 mg to about 50 mg, from about 10 mg to about 50 mg, from about20 mg to about 30 mg, or from about 1 mg to about 20 mg, followed by arest.

In one embodiment, a salt or solid form provided herein and a secondactive ingredient are administered orally, with administration of thecompound provided herein occurring 30 to 60 minutes prior to the secondactive ingredient, during a cycle of four to six weeks. In anotherembodiment, the combination of a compound provided herein and a secondactive ingredient is administered by intravenous infusion over about 90minutes every cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

5.8 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a salt or solid form providedherein. Pharmaceutical compositions and dosage forms can furthercomprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 20^(th) ed., Mack Publishing,Easton Pa. (2000).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are anhydrous if substantial contact withmoisture and/or humidity during manufacturing, packaging, and/or storageis expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

5.8.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 20th ed., Mack Publishing, Easton Pa. (2000).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a salt or solidform provided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

5.8.2 Controlled Release Dosage Forms

Active ingredients such as the compounds, salts and solid forms providedherein can be administered by controlled release means or by deliverydevices that are well known to those of ordinary skill in the art.Examples include, but are not limited to, those described in U.S. Pat.Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719;5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476;5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356;5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943;6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961;6,589,548; 6,613,358; 6,699,500 each of which is incorporated herein byreference. Such dosage forms can be used to provide slow or controlledrelease of one or more active ingredients using, for example,hydropropylmethyl cellulose, other polymer matrices, gels, permeablemembranes, osmotic systems, multilayer coatings, microparticles,liposomes, microspheres, or a combination thereof to provide the desiredrelease profile in varying proportions. Suitable controlled releaseformulations known to those of ordinary skill in the art, includingthose described herein, can be readily selected for use with the activeingredients provided herein. Thus, the compositions provided encompasssingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. Ideally, the use of an optimally designed controlledrelease preparation in medical treatment is characterized by a minimumof drug substance being employed to cure or control the condition in aminimum amount of time. Advantages of controlled release formulationsinclude extended activity of the drug, reduced dosage frequency, andincreased subject compliance. In addition, controlled releaseformulations can be used to affect the time of onset of action or othercharacteristics, such as blood levels of the drug, and can thus affectthe occurrence of side (e.g., adverse) effects.

Most controlled release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

In certain embodiments, the drug may be administered using intravenousinfusion, an implantable osmotic pump, a transdermal patch, liposomes,or other modes of administration. In one embodiment, a pump may be used(see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald etal., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574(1989)). In another embodiment, polymeric materials can be used. In yetanother embodiment, a controlled release system can be placed in asubject at an appropriate site determined by a practitioner of skill,i.e., thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138(1984)). Other controlled release systems are discussed in the review byLanger (Science 249:1527-1533 (1990)). The active ingredient can bedispersed in a solid inner matrix, e.g., polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol and cross-linked partiallyhydrolyzed polyvinyl acetate, that is surrounded by an outer polymericmembrane, e.g., polyethylene, polypropylene, ethylene/propylenecopolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetatecopolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber,chlorinated polyethylene, polyvinylchloride, vinylchloride copolymerswith vinyl acetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble inbody fluids. The active ingredient then diffuses through the outerpolymeric membrane in a release rate controlling step. The percentage ofactive ingredient in such parenteral compositions is highly dependent onthe specific nature thereof, as well as the needs of the subject.

5.8.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Salts and solid forms that increase the solubility of one or more of theactive ingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

5.8.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences,16^(th), 18^(th) and 20^(th) eds., Mack Publishing, Easton Pa. (1980,1990 and 2000); and Introduction to Pharmaceutical Dosage Forms, 4thed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16^(th), 18^(th) and 20^(th) eds., MackPublishing, Easton Pa. (1980, 1990 and 2000).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition

5.9 Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise additional active ingredients such asoblimersen (Genasense), melphalan, G-CSF, GM-CSF, EPO, topotecan,dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline,ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine,isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutantor derivative thereof, or a combination thereof. Examples of theadditional active ingredients include, but are not limited to, thosedisclosed herein.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

6. EXAMPLES 6.1 Salts and Solvates of Compound (I-S)

6.1.1 Synthesis of Compound (I-S)

Besylate of Compound (I-S) (75 g, 1×) and sodium bicarbonate (11.4 g,0.15×) were added to methyl acetate (1350 mL, 18×) and water (300 mL,4×) in a 3 liter jacketed bottom drop vessel with overhead agitation andnitrogen blanket. The mixture was agitated at 15 to 25° C. until thesolid dissolved. The mixture was settled and split. Water (75 mL, 1×)was added to the organic phase, agitated for 5 minutes at 15 to 25° C.,settled, and split. The organic layer was dried to provide Compound(I-S).

6.1.2 Freebase Anhydrate

In a vial, ˜50 mg of Compound (I-S) and ˜250 μL of acetonitrile wereheated to ˜40° C., then cooled to room temperature. The resulting slurrywas filtered, affording Compound (I-S) freebase anhydtrate solids.

6.1.3 Freebase Hydrate

In a vial, ˜150 mg of Compound (I-S) and ˜1.5 mL water were heated to50° C., and then cooled to room temperature. The resulting slurry wasfiltered, affording Compound (I-S) freebase hydrate solids.

6.1.4 Freebase THF Solvate

In a vial, ˜50 mg of Compound (I-S) and ˜250 μL THF were heated to 40°C., then cooled to room temperature. The resulting slurry was filtered,affording a THF solvate of Compound (I-S).

6.1.5 Besylate

Compound (II) (175 g, 1×) and benzenesulfonic acid (68.7 g 0.39×) werecharged to acetonitrile (1400 mL, 8×)

The mixture was distilled at 90° C. at a rate of 1 to 3× volume ofacetonitrile per hour for 4 hours. Seeds (1.75 g, 0.01×, as a slurry in17.5 mL of acetonitrile) were added. The mixture was continuouslydistilled at a rate of 1 to 3× volume of acetonitrile per hour for 4 to5 additional hours (8 to 9 hours total). The mixture was cooled to 15 to25° C. over about 1 to 4 hours, and agitated at 15 to 25° C. for atleast 1 hour. The solid was filtered, washed with acetonitrile (350 mL,2×), and dried under reduced pressure at 35 to 50° C. with nitrogenbleed, to afford the besylate salt of Compound (I-S).

6.1.6 Besylate DMSO Solvate

5 g of the besylate salt of Compound (I-S) is dissolved in 10 mLdimethylsulfoxide and 10 mL ethyl acetate. 50 mL of ethyl acetate wasadded over about 5 hours at room temperature, and the mixture wasagitated for 15 hours at room temperature. The reaction mixture isfiltered to obtain the solvate, which is washed with 10 mL of ethylacetate.

6.1.7 D-Tartrate

250 mg of Compound (I-S) was charged to 5 mL of acetonitrile. 83 mg (1molar equivalent) of D-tartaric acid is charged. The reaction mixturewas heated to 70° C., maintained at that temperature for 2 hours, then50° C. for 14 hours, then cooled to 20° C. The D-tartrate was filteredand dried under vacuum.

6.1.8 Hemi D-Tartrate

2 g of Compound (I-S) and 0.71 g of D-tartaric acid was added to 30 mLof acetonitrile. The mixture was heated for 60° C. for 1 hour and then75° C. for 1 hour. The mixture was then cooled to 20° C., and the hemiD-tartrate was collected.

6.1.9 L Tartrate

To a vial, 100 mg of Compound (I-S), 120 mg L-(+) tartaric acid solution(25% w/w in water), and 2 mL 2-propanol were added. The slurry was thenheated to 50° C., then cooled to room temperature. The slurry was thenfiltered and dried, affording the tartrate.

6.1.10 Tosylate

250 mg of Compound (I-S) was charged to acetonitrile. 106 mg (1equivalent) of p-toluenesulfonic acid hydrate was charged to themixture. The mixture was agitated for 1.5 hour at 70° C., 5 hr at 50°C., and 15 hr at 20° C. The solids were then filtered to obtain thetosylate.

6.1.11 (+) Camphorsulfonic Acid Salt

2 g of Compound (II) (3.82 mmol), 1.15 g (4.97 mmol) of (+)camphorsulfonate was charged to 20 mL ethyl acetate.

The mixture was heated to reflux for 28 hours, and the water was removedvia Dean Stark apparatus. The mixture was then cooled and filtered toafford the (+) camphorsulfonic acid salt.

6.2 Polymorph Screen of HCL Salt of Compound (I-S)

A polymorph screen of the Compound (I-S) HCl (hydrochloride) salt wasperformed to investigate whether different solid forms of the Compound(I-S) HCl salt could be generated under various conditions, such asdifferent solvents, temperature and humidity changes.

A total of eleven unique crystalline forms were found for the HCl saltin this polymorphism study. Form A was only anhydrate form found in thisstudy. All other forms were found to be either hydrate or solvate.

A polymorph screen was initiated in an attempt to generate as many solidforms as possible. Characterization of the crystal forms produced duringthe screen was performed by X-ray powder diffraction (XRPD),differential scanning calorimetry (DSC), thermogravimetric analysis(TGA), Miniature Scanning Electron Microscope (Mini SEM) and dynamicvapor sorption (DVS). Information on solubility in aqueous and variouscommon organic solvents was also obtained. A description of theexperimental procedures employed in the screen are described below.

6.2.1 Approximate Solubility

The solvents used in the polymorph screen were either HPLC or reagentgrade, including acetone, acetonitrile (MeCN), MeCN/water (1:1),n-butanol (n-BuOH), absolute ethanol (EtOH), ethanol/water (1:1),methanol (MeOH), 2-propanol (IPA), ethyl acetate (EtOAc),dichloromethane (DCM), methyl ethyl ketone (MEK), methyl t-butyl ether(MTBE), heptane, toluene, methyl acetate (MeOAc), tetrahydrofuran (THF),THF/water (1:1) and water. A weighed sample of the Compound (I-S) HClsalt (about 100 mg) was treated with a known volume of a test solvent.The resulting mixture was agitated for at least 24 hours at roomtemperature. If all of the solids appeared to be dissolved by visualinspection, the estimated solubility was calculated based on the totalvolume of solvent used to give a complete solution. If solids werepresent, a known volume of filtrate was evaporated to dryness and theweight of the residue was measured to estimate the solubility.

6.2.2 Equilibrium/Slurry and Evaporation

Equilibration and evaporation experiments were carried out by adding anexcess of the HCl salt to up to 2 mL of a test solvent. The resultingmixture was agitated for at least 24 hours at room temperature and 50°C. separately. Upon reaching equilibrium, the saturated supernatantsolution was removed, filtered using 0.45 μm PTFE filters and allowed toevaporate in an open vial under nitrogen at room temperature and 50° C.,respectively. The solid resulting from the equilibration was isolatedand air-dried before analysis.

6.2.3 Recrystallization

For cooling recrystallization, the selected solvent (MeOH) was saturatedwith the HCl salt at 60° C. The solution was stirred at 60° C. for 10minutes, filtered using a 0.45 μm PTFE syringe filter, and then cooledto room temperature at 20° C./min stay overnight. The solution wasplaced into a refrigerator for 5 days. The solid resulting from therecrystallization was isolated and air-dried before analysis.

For anti-solvent recrystallization, the selected solvents (DMSO andMeOH) were saturated with the HCl salt at 60° C. Once the solid wascompletely dissolved, a portion of the solution was filtered into ananti-solvent (Acetone, MeCN, BuOAc, n-BuOH, MTBE, toluene or THF). Themixture of DMSO/MTBE and DMSO/THF were stirred at room temperatureovernight. The rest of solutions was placed into a refrigerator for 5days. The solid resulting from the recrystallization was isolated andair-dried before analysis.

6.2.4 Characterization

(A) X-Ray Powder Diffraction (XRPD)

All of the solid samples generated in the polymorph screen were analyzedby XRPD. XRPD analysis was conducted on a PANalytical Empyrean or aThermo ARL X′TRA X-ray powder diffractometer using Cu Kα radiation at1.54 Å.

The PANalytical Empyrean instrument was equipped with a fine focus X-raytube. The voltage and amperage of the X-ray generator were set at 45 kVand 40 mA, respectively. The divergence slits were set at 1/16° and ⅛°,and the receiving slits was set at 1/16°. Diffracted radiation wasmeasured using a Pixel 2D detector. A theta-two theta continuous scanwas set at step size 0.013 or 0.026 from 3° to 40° 2θ with samplespinning rate at 4. A sintered alumina standard was used to check thepeak positions.

The Thermo ARL X'TRA instrument was equipped with a fine focus X-raytube. The voltage and amperage of the X-ray generator were set at 45 kVand 40 mA, respectively. The divergence slits were set at 4 mm and 2 mmand the measuring slits were set at 0.5 mm and 0.2 mm. Diffractedradiation was measured using a Peltier-cooled Si (Li) solid-statedetector. A theta-two theta continuous scan at 2.40°/min (0.5 sec/0.02°step) from 1.5° to 40° 2θ was used. A sintered alumina standard was usedto check the peak positions.

(B) Differential Scanning Calorimetry (DSC)

DSC analyses were performed on a TA instrument Q2000 DifferentialScanning calorimeter. Indium was used as the calibration standard.Approximately 2-5 mg of sample was placed into a DSC pan. The sample washeated under nitrogen at a rate of 10° C./min, up to a final temperatureof 300° C. Melting points were reported as the extrapolated onsettemperatures.

(C) Thermogravimetric Analysis (TGA)

TGA analyses were performed on a TA instrument Q5000 ThermogravimetricAnalyzer. Calcium oxalate was used for a performance check.Approximately 2-10 mg of accurately weighed sample was placed on a panand loaded into the TGA furnace. The sample was heated under nitrogen ata rate of 10 degrees C./min, up to a final temperature of 300 degrees C.

(D) Miniature Scanning Electron Microscope (Mini SEM)

Morphology analysis of the samples was carried out on an Even Mini SEM.Small amounts of samples were dispersed on a sample holder, and thencoating with gold viewed with 200× and 1000× magnification.

(E) Dynamic Vapor Sorption (DVS)

Hygroscopicity was determined on a Surface Measurement Systems DVS.Typically a sample size of 5-30 mg was loaded into the DVS instrumentsample pan and the sample was analyzed on a DVS automated sorptionanalyzer at room temperature. The relative humidity was increased from0% to 90% RH at 10% RH step, then at 95% RH. The relative humidity wasthen decreased in a similar manner to accomplish a fulladsorption/desorption cycle. For hydrated forms, the analysis started at50% RH and increased to 90% RH at 10% RH step. The relative humidity wasthen decreased in a similar manner to 0% RH followed by increasing to50% RH.

(F) Nuclear Magnetic Resonance (NMR)

¹H NMR spectra were obtained on a Bruker 300 MHz NMR spectrometer.Samples were dissolved in DMSO-d6 and analyzed with 64 to 128 scans. TheForm C sample was dissolved in MeOD.

6.2.5 Results

Approximate solubility of the HCl salt Form A, in various solvents atambient temperature was estimated as described. The results aresummarized in Table 1.

TABLE 1 Approximate Solubility of HCl Salt Form A in Selected Solventsat Room Temperature. Approximate Solubility Solvent (mg/mL) Acetone <1CH₃CN <1 n-BuOH <1 EtOH ~1 MeOH ~10 IPA ~1 EtOAc <1 MEK <1 CH₂Cl₂ <1MTBE <1 Heptane <1 Toluene <1 MeOAc <1 THF <1 H₂O >50 CH₃CN/H₂O(1:1) >50 EtOH/H₂O (1:1) >50 THF/H₂O (1:1) >50 DMSO >50

The HCl salt was found to be most soluble (greater than 50 mg/mL) inMeCN/water (1:1), EtOH/water (1:1), THF/water (1:1), and water. The HClsalt showed moderate solubility in MeOH. The HCl salt showed low or verylow solubility (around or less than 1 mg/mL) in acetone, MeCN, n-BuOH,EtOH, IPA, EtOAc, MEK, DCM, MTBE, heptane, MeOAc, toluene and THF.

The XRPD pattern of the HCl salt drug substance used to generate samplesin the polymorph screen is shown in FIG. 94 and FIG. 35. The crystallinepattern was designated as Form A.

Equilibration experiments were performed at room temperature and 50° C.using the HCl salt Form A as starting material. The results aresummarized in Table 2.

TABLE 2 Equilibration of Form A at Room Temperature and 50° C. Form byXRPD Solvent RT 50° C. Acetone A A CH₃CN A A n-BuOH A A EtOH A A MeOH AA IPA A A EtOAc A A MEK A A CH₂Cl₂ A n/a MTBE A A Heptane A A Toluene AA MeOAc A A THF A A H₂O n/a n/a CH₃CN/H₂O (1:1) n/a n/a EtOH/H₂O (1:1)n/a n/a THF/H₂O (1:1) n/a n/a Acetone/H₂O (95:5) A n/a MeCN/H₂O (95:5) Dn/a EtOH/H₂O (95:5) A n/a IPA/H₂O (95:5) A n/a MeOAc/H₂O (95:5) A n/aTHF/H₂O (95:5) A n/a n/a: all solid went in solution or experiment notperformed.

All of the solids isolated from non-aqueous solvents after 24 h ofslurry were confirmed to be Form A by XRPD. Since all solid in aqueousor 50/50 mixtures of aqueous/organic solvent mixtures went in solution,additional equilibration experiments were performed in organic/watermixtures containing 5% of water at room temperature, includingacetone/water, MeCN/water, EtOH/water, IPA/water, MeOAc/water andTHF/water. All solids isolated were confirmed to be Form A by)(RFD,except for the solid from MeCN/water. The unique XRPD pattern obtainedfrom this condition was designated as Form D

Evaporation experiments were performed at room temperature and 50° C.The results are summarized in Table 3.

TABLE 3 Evaporation of Form A at Room Temperature and 50° C. Form byXRPD Solvent RT 50° C. Acetone — — CH₃CN — — n-BuOH — — EtOH — — MeOH —A IPA — — EtOAc — — MEK — — CH₂Cl₂ — — MTBE — — Heptane — — Toluene — —MeOAc — A THF — — H₂O Amorphous Amorphous CH₃CN/H₂O Amorphous AmorphousEtOH/H₂O Amorphous Amorphous THF/H₂O Amorphous Amorphous —Not analyzable

Since the solubility of the HCl salt was low in most organic testingsolvents, residual solids obtained from these solvents were not enoughfor any analysis. Evaporation from MeOH and MeOAc afforded solids thatwere confirmed to be Form A by XRPD. The solids isolated from water orwater/organic mixtures evaporation at room temperature and 50° C. allshowed amorphous XRPD pattern.

Cooling recrystallization and recrystallizations with anti-solvents wereperformed. MeOH was used as single solvent for coolingrecrystallization. For anti-solvent recystallization, DMSO or MeOH wasused as primary solvent, and acetone, MeCN, MTBE, BuOAc, n-BuOH, tolueneor THF used as anti-solvent. The results are summarized in Table 4.

TABLE 4 Summary of Recrystallization Experiments. Primary solventAnti-Solvent Solvent ratio Form by XRPD MeOH n/a n/a B MeOH CH₃CN 1:3n/a MeOH BuOAc 1:3 n/a MeOH MTBE 1:3 G MeOH Toluene 1:3 H MeOH THF 1:3n/a DMSO CH₃CN  1:10 I DMSO BuOAc  1:10 C + peaks* DMSO n-BuOH  1:10 CDMSO MTBE  1:10 C + peaks* DMSO Acetone  1:10 I DMSO THF  1:10 J n/a:not analyzable. *additional diffraction peaks observed but notdefinitively identifiable.

Solid from MeOH showed unique XRPD pattern designated as Form B. TheXRPD patterns for solids from MeOH//MTBE and MeOH/toluene showed similardiffraction peaks, but were later identified as different solid forms,designated as Form G and Form H, respectively. Solid from DMSO/n-BuOH,DMSO/MTBE and DMSO/BuOAc showed unique XRPD pattern designated as FormC. Solid from DMSO/Acetone or DMSO/MeCN showed unique XRPD patterndesignated as Form I. And the pattern for solid from DMSO/THF wasdesignated as Form J.

Further form conversion experiments were performed to determineinterconversion among solid forms. Form conversion was also observedduring further characterization of the solid forms. The results aresummarized in Table 5.

TABLE 5 Stability and Form Transfer Experiments of HCl salt StartingForm Solvent/Condition Time at RT XRPD Result Form B Exposed to ambientair 1 week Form A Form C MeOAc 1 day Form A Form D MeCN/water (95:5) 10day Form D Form B After DVS — Form A Form C After DVS — Form A Form DAfter DVS — Form F Form B IPA 24 h Form A Form C IPA 24 h Form A Form DIPA 24 h Form A Form E IPA 24 h Form A Form F IPA 10 days Form A Form IMeoAc 1 minute Form A

Competitive slurry experiments were carried out of Forms E and F. Theresults are summarized in Table 6.

TABLE 6 Summary of HCl Salt Form E and Form F Transformation. StartingForm Solvent/Condition Time at RT XRPD Result Form E IPA/water (40/60)Spontaneous Form F Form E IPA/water (60/40) Spontaneous Form F Form EIPA/water (80/20) Spontaneous Form F Form E IPA/water (90/10)Spontaneous Form F Form E IPA/water (95/5)  Spontaneous Form F Form A +F IPA/water (50/50) 3 days Form A Form A + F IPA/water (65/35) 3 daysForm A Form A + F IPA/water (80/20) 6 days Form A Form A + F IPA/water(95/5)  6 days Form A Form A + F Water 3 days Form A Form A + F MeOAcsaturated with 3 days Form A water

6.2.6 Characterization of Polymorphic Forms

A total of eleven crystalline forms of the HCl salt were found duringthis polymorph screen study. The stack plot of XRPD patterns for theseforms are shown in FIG. 105, and the physical characteristics aresummarized in Table 7.

TABLE 7 Summary of Physical Characterization of HCl Salt CrystallineForms. Representative DSC onset or TGA DVS or other Form Descriptionconditions peak (° C.) (wt %) comments A Anhydrate salt formation in 256(onset) ~0.16 1.8 wt % water uptake IPA/water/MeOAc from 0 to 90% RH BHydrate/ MeOH ~80 (broad), 7.6 Converts to Form A solvaterecrystallization 174 (endo), during exposure to ~250 (peak) ambient CSolvate/ DMSO/(n-BuOH, ~50 (broad), 1.6, Converts to Form A at hydrateMTBE or BuoAc) 142 (endo), 15.1 high humidity recrystallization 146(endo), ~250 (onset) D Hydrate MeCN/water slurry ~60 (broad), 9.2Converts to Form F at 169 (endo), high humidity during ~250 (onset) DVSexperiment E Hydrate salt formation in 111 (broad), 4.5 Converts to FormF MeCN/water 185 (endo), during DVS experiment ~250 (onset) F Hydratesalt formation in 83 (broad), 5.0 5.3~6.3 wt % water IPA/water 217(endo), between 10 to 90% RH; ~250 (onset) 5.3 wt % mass change from 10to 0% RH G Solvate/ MeOH/MTBE 199 (endo), 1.9, Partially converted tohydrate recrystallization 248 (peak) 12.3 Form A during DVS experiment HSolvate/ MeOH/Toluene 187 (endo), 0.3, n/a hydrate recrystallization 255(peak) 15.3 I Solvate/ DMSO/(MeCN, n/a n/a Converts to Form A hydrateacetone) upon exposure to recrystallization ambient humidity J Solvate/DMSO/THF ~70 (broad), 4.7, n/a hydrate recrystallization 106 (endo),7.6, 127 (endo), 10.2 251 (onset) K Dehydrate Dehydrated from n/a n/aConverts to Form F Form F upon exposure to ambient humidity n/a: notavailable.

(A) Form A

To a vial, 100 mg of a hydrate of the HCl salt of Compound (I-S) and 2mL 2-propanol were added. The slurry was heated to 75° C. An additional2 mL 2-propanol was added to thin out the resulting slurry. The batchwas then cooled to room temperature and the slurry was filtered anddried, affording Form A, an anhydrate of a HCl salt of Compound (I-S).Form A was also found from most equilibration and evaporationexperiments performed in this study. Form A had a crystalline XRPDpattern as shown in FIG. 36 and an irregular rod crystal habit as shownin FIG. 37. DSC and TGA thermograms of Form A are shown in FIG. 38 andFIG. 39, respectively. The DSC thermogram showed only one major eventwith an onset temperature of 256° C., corresponding tomelt/decomposition. A TGA weight loss of 0.16% up to ˜120° C. wasobserved. The ¹H-NMR spectrum of Form A was consistent with Compound(I-S) structure with a small amount of residual solvent (FIG. 40).Without being limited by any particular theory, based on these data,Form A is an anhydrate.

The moisture sorption/desorption behavior of Form A was determined byDVS and the results are summarized in FIG. 41. A total mass change of1.8% was observed between 0% RH and 95% RH, suggesting Form A isslightly hygroscopic. After undergoing the adsorption/desorption cycles,the XRPD diffractogram of the sample showed no change (FIG. 42).

The stability of Form A was further characterized by compression testand form transfer experiments. Upon application of 2000-psi pressure forabout 1 minute, the material was still Form A (FIG. 43). Results fromform transfer experiments (Tables 5 and 6) showed that all hydrate andsolvate form will convert to Form A in IPA slurry. Furthermore Form A isalso the more stable than hydrate forms in water and aqueous/organicmixtures studied. Without being limited by any particular theory, theseresults suggested that Form A is a stable anhydrate form of the HClsalt.

(B) Form B

Form B was obtained from recrystallization of Form A in MeOH. Form B hada crystalline XRPD pattern as shown in FIG. 44 and irregular rod crystalhabit as shown in FIG. 45. DSC and TGA thermograms of Form B are shownin FIG. 46 and FIG. 47, respectively. The TGA weight loss of 7.6 wt %corresponded to broad DSC broad peak around 80° C. can be attributed toloss of water/solvent in Form B. The DSC thermogram also showedendothermic peaks at 174 and 250° C., respectively. The ¹H-NMR spectrumwas obtained for the Form B sample and did not show significantdegradation or residual solvent (FIG. 48). Form B sample was found tohave converted to Form A upon ambient storage (FIG. 49). Without beinglimited by any particular theory, based on available characterizationdata, Form B is a hydrate of the Compound (I-S) HCl salt.

(C) Form C

Form C was obtained from anti-solvent recrystallization in DMSO/n-BuOH,DMSO/MTBE or DMSO/BuOAc. Form C had a crystalline XRPD pattern as shownin FIG. 50 and irregular crystal habit as shown in FIG. 51. DSC and TGAthermograms of Form C are shown in FIG. 52 and FIG. 53, respectively.The TGA weight loss of 1.6 and 15.1 wt % corresponded to broad DSCendotherm around 50° C. and endotherms around 142-146° C., respectively,and can be attributed to loss of solvent/water in Form C. The DSCthermogram with an onset temperature of 251.8° C. was due to finalmelt/decomposition. To further confirm the desolvation event observed, aForm C sample was heated to 165° C. and tested for XRPD. The XRPDpattern of the heated sample was consistent with Form A (FIG. 54). The¹H-NMR spectrum of Form C was consistent with Compound I structure withapproximately one molar equivalent (or ˜13.9 wt %) of DMSO solvent (FIG.55). Without being limited by any particular theory, Form C is a DMSOsolvate.

The Form C sample was found to convert to Form A upon exposure to highhumidity (higher than 70% RH) in the DVS instrument (FIG. 56). Form Cwas also found to convert to Form A in IPA slurry (Table 5).

(D) Form D

Form D was obtained from equilibration of Form A in MeCN/water (95:5).Form D had a crystalline XRPD pattern as shown in FIG. 57 and irregularcrystal habit as shown in FIG. 58. DSC and TGA thermograms of Form D areshown in FIG. 59 and FIG. 60, respectively. The TGA weight loss of 9.2wt % corresponded to the broad DSC endotherm around 60° C. The DSCthermogram also showed endothermic peaks at 169 and 250° C. The ¹H-NMRspectrum of Form D was consistent with Compound (I-S) structure withoutsignificant degradation or residual solvent (FIG. 61). Without beinglimited by any particular theory, Form D is a hydrate.

The moisture sorption/desorption behavior of Form D was determined byDVS and the results are summarized in FIG. 62. Form D exhibited a masschange of ˜11% relative to the dry mass when the relative humidity wasincreased from 50 to 80% RH, suggesting Form D is hygroscopic material.A steep mass change of ˜12% was observed between 80-90% RH duringadsorption, most likely due to transformation of solid form. Afterundergoing the adsorption/desorption cycles, the XRPD diffractogram ofthe sample showed that the material was changed from the initial Form Dto Form F (FIG. 63). This result explained why the desorption curve andthe second adsorption curve obtained for Form D were similar to those ofForm F. These observations suggested that Form D was a less stablehydrate than Form F.

(E) Form E

To a flask, 1 g of Compound (I-S), 19 mL of acetonitrile, and 1 mL waterwere added and heated to 45° C. to dissolve the solid. Thenapproximately 0.4 mL of 6 M HCl was added and the batch was cooled toroom temperature. The batch was held at room temperature untilprecipitation occurred, upon which the batch was reheated to 45° C.Then, the batch was cooled to room temperature, filtered, and dried,affording Form E, a hydrate of a HCl salt of Compound (I-S). Form E hada crystalline XRPD pattern as shown in FIG. 64 and irregular crystalhabit as shown in FIG. 65. DSC and TGA thermograms of Form E are shownin FIG. 66 and FIG. 67, respectively. The TGA weight loss of 4.5 wt %corresponded to the broad DSC endotherm around 100° C. and alsocorresponded to the Karl Fischer result which showed 4.2 wt % of water.Without being limited by any particular theory, Form E is a hydrate. TheDSC thermogram showed an endotherm around 185° C. and the finalmelt/decomposition around 250° C. The ¹H-NMR spectrum of Form E wasconsistent with Compound (I-S) structure without significant degradationor residual solvent (FIG. 68).

The moisture sorption/desorption behavior of Form E was determined byDVS and the results are summarized in FIG. 69. Form E exhibited a masschange of ˜14% relative to the dry mass when the relative humidity wasincreased from 50 to 80% RH, suggesting Form E is hygroscopic. A steepmass change was observed between 80-90% RH during adsorption, mostlikely due to transformation of solid form. After undergoing theadsorption/desorption cycles, the XRPD diffractogram of the sampleshowed that the material partially converted to Form F (FIG. 70).

Form E sample was heated to 120° C. and analyzed for XRPD. The resultedXRPD pattern was consistent with Form E, suggesting Form E lattice wasstable upon moderate heating. Furthermore, a Form E sample was heated to190° C. and resulted in an amorphous pattern, confirming that theendothermic event at 185° C. was corresponding to melting or collapsingof crystal lattices in Form E. Data are provided in FIGS. 71 and 82.

Form transfer experiments showed that Form E converted to Form A in IPAslurry (Table 5). Form E was also found to convert to Form F in variousIPA/water mixtures (Table 6).

(F) Form F

To a flask, 2.5 g of Compound (I-S), 5 mL of 2-propanol and 7.5 mL waterwere added. Approximately 0.5 mL concentrated HCl was then added. Thebatch was heated to 40° C. and then cooled to 25° C. Approximately 50 mL2-propanol was added dropwise, causing crystallization. The slurry wasfiltered and dried, affording a hydrate of a HCl salt of Compound (I-S).Form F was also spontaneously formed when Form E was slurried inIPA/water solvent mixtures. Form F had a crystalline XRPD pattern asshown in FIG. 73 and irregular rod crystal habit as shown in FIG. 74.DSC and TGA thermograms of Form F are shown in FIG. 75 and FIG. 76,respectively. The TGA weight loss of 5.0 wt % corresponded to the broadDSC endotherm around 83° C. and also corresponded to the Karl Fischerresult which showed 5.3 wt % of water. Without being limited by anyparticular theory, Form F is a hydrate. The measured water contentcoincided with the theoretical water content of a sesqui-hydrate of theHCl Compound (I-S) salt. The DSC thermogram also showed an endothermaround 217° C. and the final decomposition around 250° C. The ¹H-NMRspectrum of Form F was consistent with Compound (I-S) structure withoutsignificant degradation or residual solvent (FIG. 77).

The moisture sorption/desorption behavior of Form F was determined byDVS and the results are summarized in FIG. 78. Form F exhibited a totalmass change of 6.3% relative to the dry mass when the relative humiditywas increased from 0 to 90% RH. The water content was stabilized between5.2 to 6.3 wt % from 10 to 90% RH, corresponding to approximately1.5˜1.8 molar equivalent of water. A steep mass change of 5.2 wt % wasobserved between 10-0% RH during desorption. After undergoing theadsorption/desorption cycles, the XRPD diffractogram of the sampleshowed that the material was unchanged from the initial Form F (FIG.79).

The form transfer experiments showed that Form F convert to Form A whenin IPA slurry (Table 5). Competitive slurry experiments listed in Table6 also showed that Form F is less stable than Form A is variousaqueous/IPA mixtures. To further probe the stability of Form F, a Form Fsample was heated to 120° C. and analyzed for XRPD. The resulted XRPDpattern was consistent with Form F (FIG. 80). The TGA plot of the heatedsample showed 4.9 wt % weight loss (FIG. 81), consistent with expectedwater content in Form F. Further, a Form F sample was placed in achamber containing drierrite for 16 hours, the resulted solid provided aunique XRPD pattern designated as Form K.

(G) Form G

Form G was obtained from recrystallization of Form A in MeOH/MTBE. FormG had a crystalline XRPD pattern as shown in FIG. 82. The pattern showedsome similarity to those of Form B and Form H, but was found to be adifferent solvate form. DSC and TGA thermograms of Form G are shown inFIG. 83 and FIG. 84, respectively. The initial TGA weight loss of 1.9 wt% corresponded to broad DSC broad peak around 60° C. and was likelyattributed to loss of surface water/solvent in Form G. The major TGAweight loss of 12.3 wt % corresponded to the DSC endothermic peak at199° C. The ¹H-NMR spectrum was obtained for the Form G sample andshowed approximately 0.5 molar equivalent (or ˜8.3 wt %) of MTBE (FIG.85). Without being limited by any particular theory, Form G is a MTBEsolvate of the Compound (I-S) HCl salt.

(H) Form H

Form H was obtained from recrystallization of Form A in MeOH/toluene.Form H had a crystalline XRPD pattern as shown in FIG. 86. The patternshowed some similarity to Form B and was almost identical to Form G, butwas found to be a different solvate form. DSC and TGA thermograms ofForm H are shown in FIG. 87 and FIG. 88, respectively. The major TGAweight loss of 15.3 wt % corresponded to the DSC endothermic peak at187° C. The ¹H-NMR spectrum was obtained for the Form H sample andshowed approximately 0.8 molar equivalent (or ˜13.2 wt %) of toluene(FIG. 89). Without being limited by any particular theory, Form H is atoluene solvate of the Compound (I-S) HCl salt.

(I) Form I

Form I was obtained from recrystallization of Form A in DMSO/MeCN orDMSO/acetone. Form I had a crystalline XRPD pattern as shown in FIG. 90.The Form I was found to change to Form A. During crystallizationexperiments, some Form I solid was washed with MeOAc as an attempt toremove residual DMSO. The XRPD pattern of the resulted solid wasconsistent with Form A (FIG. 91). Without being limited by anyparticular theory, Form I is a solvate of the Compound (I-S) HCl salt.

(J) Form J

Form J was obtained from recrystallization of Form A in DMSO/THF. Form Jhad a crystalline XRPD pattern as shown in FIG. 92. DSC and TGAthermograms of Form J are shown in FIGS. 93 and 94, respectively. Theinitial TGA weight loss of 4.7 wt % corresponded to broad DSC broad peakaround 70° C. and was likely attributed to loss of surface water/solventin Form J. The TGA weight losses of 7.6 and 10.3 wt % corresponded tothe DSC endothermic peaks at 106 and 127° C., respectively. Withoutbeing limited by any particular theory, Form J a solvate of the HClsalt.

(K) Form K

Form K was obtained from drying Form F at close to 0% RH condition. Indetail, a Form F sample was placed in a chamber containing drierite for16 hours. The resulted solid afforded a unique XRPD pattern, as shown inFIG. 95. Form K was not available as the Form was observed to convert toForm F after exposure to ambient condition (FIG. 96).

6.3 Salts and Solvates of Racemic Compound (I)

6.3.1 Freebase Anhydrate

In a vial, ˜50 mg of racemic Compound (I) and ˜250 uL acetonitrile wereheated to 40° C., then cooled to room temperature. The resulting slurrywas filtered, affording racemic Compound (I) freebase anhydrate solids.

6.3.2 Freebase Hydrate

In a vial, ˜50 mg racemic Compound (I) and ˜250 μL 1/1acetonitrile/water were heated to 40° C., then cooled to roomtemperature. The resulting slurry was filtered, affording racemicCompound (I) freebase hydrate solids.

6.3.3 Hydrochloride Hydrate

In a vial, ˜750 mg racemic Compound (I) hydrochloride and ˜15 mL 80/20isopropanol/water were heated to 50° C., then cooled to roomtemperature. The resulting slurry was filtered, affording racemicCompound (I) hydrochloride hydrate solids.

6.3.4 Hydrochloride Methanol Solvate

In a vial, ˜70 mg racemic Compound (I) hydrochloride and 1 mL methanoldried on 3-A molecular sieves were added. The suspension was heated to50° C., then cooled to room temperature. The resulting slurry wasfiltered, affording a wet solids of racemic Compound (I) hydrochloridemethanol solvate. The product was converted to racemic Compound (I)hydrochloride hydrate upon exposure to ambient moisture.

6.4 Assays

6.4.1 TNFα Inhibition Assay in hPMBC

Human peripheral blood mononuclear cells (hPBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 μg/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat. no. L-1887, St.Louis, Mo., USA) at 1 ng/ml final in the absence or presence ofcompounds. Compounds provided herein are dissolved in DMSO (Sigma) andfurther dilutions are done in culture medium immediately before use. Thefinal DMSO concentration in all assays can be about 0.25%. Compounds areadded to cells 1 hour before LPS stimulation. Cells are then incubatedfor 18-20 hours at 37° C. in 5% CO₂, and supernatants are thencollected, diluted with culture medium and assayed for TNFα levels byELISA (Endogen, Boston, Mass., USA). IC₅₀s are calculated usingnon-linear regression, sigmoidal dose-response, constraining the top to100% and bottom to 0%, allowing variable slope (GraphPad Prism v3.02).

6.4.2 IL-2 and MIP-3a Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 μl anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μl in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3a by ELISA (R&DSystems). IL-2 and MIP-3a levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

6.4.3 Cell Proliferation Assay

Cell lines (e.g., Namalwa, MUTZ-5, UT-7, and various NHL cell lines) areobtained from the Deutsche Sammlung von Mikroorganismen and ZellkulturenGmbH (Braunschweig, Germany). The cell line KG-1 is obtained from theAmerican Type Culture Collection (Manassas, Va., USA). Cellproliferation as indicated by ³H-thymidine incorporation is measured inall cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

6.4.4 Immunoprecipitation and Immunoblot

Cells (e.g., various NHL cell lines) are treated with DMSO or an amountof a compound provided herein for 1 hour, then stimulated with 10 U/mlof Epo (R&D Systems) for 30 minutes. Cell lysates are prepared andeither immunoprecipitated with Epo receptor Ab or separated immediatelyby SDS-PAGE. Immunoblots are probed with Akt, phospo-Akt (Ser473 orThr308), phospho-Gabl (Y627), Gabl, IRS2, actin and IRF-1 Abs andanalyzed on a Storm 860 Imager using ImageQuant software (MolecularDynamics).

6.4.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

6.4.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

6.4.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of AP1-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to the claimed subjectmatter. The full scope of the invention is better understood withreference to the appended claims.

What is claimed:
 1. A method of treating cancer, an immune-relateddisease or disorder, an inflammatory disease or disorder, or a symptomthereof in a subject, comprising administering to the subject atherapeutically effective amount of a solid form comprising a racemicCompound (I):

or a hydrate or anhydrate thereof, wherein the solid form iscrystalline, wherein the solid form comprises a HCl salt of racemicCompound (I) and water, having an XRPD pattern comprising peaks atapproximately 13.88, 14.30, and 15.36 degrees 2θ; or comprises a HClsalt of racemic Compound (I) and methanol, having an XRPD patterncomprising peaks at approximately 12.38, 14.54, and 26.10 degrees 2θ;wherein the cancer, immune-related disease or disorder, or inflammatorydisease or disorder is lupus, scleroderma, Sjögren syndrome,ANCA-induced vasculitis, anti-phospholipid syndrome, myasthenia gravis,or multiple myeloma.
 2. The method of claim 1, wherein the solid formcomprises a HCl salt of racemic Compound (I) and water, having an XRPDpattern comprising peaks at approximately 13.88, 14.30, and 15.36degrees 2θ.
 3. The method of claim 2, wherein the XRPD pattern furthercomprises peaks at approximately 9.84, 16.42, and 19.82 degrees 2θ. 4.The method of claim 2, wherein the XRPD pattern matches the XRPD patternpresented in FIG.
 101. 5. The method of claim 1, wherein the solid formcomprises a HCl salt of racemic Compound (I) and methanol, having anXRPD pattern comprising peaks at approximately 12.38, 14.54, and 26.10degrees 2θ.
 6. The method of claim 5, wherein the XRPD pattern furthercomprises peaks at approximately 15.06, 20.00, and 26.86 degrees 2θ. 7.The method of claim 5, wherein the XRPD pattern matches the XRPD patternpresented in FIG.
 104. 8. The method of claim 1, wherein theimmune-related or inflammatory disease or disorder is lupus,scleroderma, Sjögren syndrome, ANCA-induced vasculitis,anti-phospholipid syndrome, or myasthenia gravis.
 9. The method of claim1, wherein the immune-related or inflammatory disease or disorder isscleroderma.
 10. The method of claim 1, wherein the immune-related orinflammatory disease or disorder is systemic lupus erythematosus (SLE),cutaneous lupus erythematosus (CLE), discoid lupus erythematosus (DLE),or drug-induced lupus.
 11. The method of claim 10, wherein theimmune-related or inflammatory disease or disorder is systemic lupuserythematosus (SLE).
 12. The method of claim 10, wherein theimmune-related or inflammatory disease or disorder is cutaneous lupuserythematosus (CLE).
 13. The method of claim 1, wherein the cancer ismultiple myeloma.
 14. The method of claim 1, wherein the lupus issystemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE),discoid lupus erythematosus (DLE), or drug-induced lupus.